Injectable formulations of taxanes for cad treatment

ABSTRACT

Liquid formulations, including solutions and suspensions of the various drugs, agents and/or compounds, may be locally or regionally delivered for the treatment of vascular disease. In each of these instances, antioxidants are utilized to prolong product integrity.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to the local administration of drug/drugcombinations for the prevention and treatment of vascular disease, andmore particularly to intraluminal medical devices for the local deliveryof drug/drug combinations for the prevention and treatment of vasculardisease caused by injury and methods and devices for maintaining thedrug/drug combinations on the intraluminal medical devices, as well aspreventing damage to the medical device. The present invention alsorelates to medical devices, including stents, grafts, anastomoticdevices, perivascular wraps, sutures and staples having drugs, agentsand/or compounds affixed thereto to treat and prevent disease andminimize or substantially eliminate a biological organism's reaction tothe introduction of the medical device to the organism. In addition, thedrugs, agents and/or compounds may be utilized to promote healing andendothelialization. The present invention also relates to coatings forcontrolling the elution rates of drugs, agents and/or compounds fromimplantable medical devices. The present invention also relates to drugsand drug delivery systems for the regional delivery of drugs fortreating vascular disease as well as liquid formulations of the drugs.The present invention also relates to medical devices having drugs,agents and/or compounds affixed thereto for treating vulnerable plaque.The present invention also relates to agents for reducing thedegradation of drugs caused by oxidation.

2. Discussion of the Related Art

Many individuals suffer from circulatory disease caused by a progressiveblockage of the blood vessels that perfuse the heart and other majororgans. More severe blockage of blood vessels in such individuals oftenleads to hypertension, ischemic injury, stroke, or myocardialinfarction. Atherosclerotic lesions, which limit or obstruct coronaryblood flow, are the major cause of ischemic heart disease. Percutaneoustransluminal coronary angioplasty is a medical procedure whose purposeis to increase blood flow through an artery. Percutaneous transluminalcoronary angioplasty is the predominant treatment for coronary vesselstenosis. The increasing use of this procedure is attributable to itsrelatively high success rate and its minimal invasiveness compared withcoronary bypass surgery. A limitation associated with percutaneoustransluminal coronary angioplasty is the abrupt closure of the vessel,which may occur immediately after the procedure and restenosis, whichoccurs gradually following the procedure. Additionally, restenosis is achronic problem in patients who have undergone saphenous vein bypassgrafting. The mechanism of acute occlusion appears to involve severalfactors and may result from vascular recoil with resultant closure ofthe artery and/or deposition of blood platelets and fibrin along thedamaged length of the newly opened blood vessel.

Restenosis after percutaneous transluminal coronary angioplasty is amore gradual process initiated by vascular injury. Multiple processes,including thrombosis, inflammation, growth factor and cytokine release,cell proliferation, cell migration and extracellular matrix synthesiseach contribute to the restenotic process.

While the exact mechanism of restenosis is not completely understood,the general aspects of the restenosis process have been identified. Inthe normal arterial wall, smooth muscle cells proliferate at a low rate,approximately less than 0.1 percent per day. Smooth muscle cells in thevessel walls exist in a contractile phenotype characterized by eighty toninety percent of the cell cytoplasmic volume occupied with thecontractile apparatus. Endoplasmic reticulum, Golgi, and free ribosomesare few and are located in the perinuclear region. Extracellular matrixsurrounds the smooth muscle cells and is rich in heparin-likeglycosylaminoglycans, which are believed to be responsible formaintaining smooth muscle cells in the contractile phenotypic state(Campbell and Campbell, 1985).

Upon pressure expansion of an intracoronary balloon catheter duringangioplasty, smooth muscle cells and endothelial cells within the vesselwall become injured, initiating a thrombotic and inflammatory response.Cell derived growth factors such as platelet derived growth factor,basic fibroblast growth factor, epidermal growth factor, thrombin, etc.,released from platelets, invading macrophages and/or leukocytes, ordirectly from the smooth muscle cells provoke a proliferative andmigratory response in medial smooth muscle cells. These cells undergo achange from the contractile phenotype to a synthetic phenotypecharacterized by only a few contractile filament bundles, extensiverough endoplasmic reticulum, Golgi and free ribosomes.Proliferation/migration usually begins within one to two days'post-injury and peaks several days thereafter (Campbell and Campbell,1987; Clowes and Schwartz, 1985).

Daughter cells migrate to the intimal layer of arterial smooth muscleand continue to proliferate and secrete significant amounts ofextracellular matrix proteins. Proliferation, migration andextracellular matrix synthesis continue until the damaged endotheliallayer is repaired at which time proliferation slows within the intima,usually within seven to fourteen days post-injury. The newly formedtissue is called neointima. The further vascular narrowing that occursover the next three to six months is due primarily to negative orconstrictive remodeling.

Simultaneous with local proliferation and migration, inflammatory cellsadhere to the site of vascular injury. Within three to seven dayspost-injury, inflammatory cells have migrated to the deeper layers ofthe vessel wall. In animal models employing either balloon injury orstent implantation, inflammatory cells may persist at the site ofvascular injury for at least thirty days (Tanaka et al., 1993; Edelmanet al., 1998). Inflammatory cells therefore are present and maycontribute to both the acute and chronic phases of restenosis.

Numerous agents have been examined for presumed anti-proliferativeactions in restenosis and have shown some activity in experimentalanimal models. Some of the agents which have been shown to successfullyreduce the extent of intimal hyperplasia in animal models include:heparin and heparin fragments (Clowes, A. W. and Karnovsky M., Nature265: 25-26, 1977; Guyton, J. R. et al., Circ. Res., 46: 625-634, 1980;Clowes, A. W. and Clowes, M. M., Lab. Invest. 52: 611-616, 1985; Clowes,A. W. and Clowes, M. M., Circ. Res. 58: 839-845, 1986; Majesky et al.,Circ. Res. 61: 296-300, 1987; Snow et al., Am. J. Pathol. 137: 313-330,1990; Okada, T. et al., Neurosurgery 25: 92-98, 1989), colchicine(Currier, J. W. et al., Circ. 80: 11-66, 1989), taxol (Sollot, S. J. etal., J. Clin. Invest. 95: 1869-1876, 1995), angiotensin convertingenzyme (ACE) inhibitors (Powell, J. S. et al., Science, 245: 186-188,1989), angiopeptin (Lundergan, C. F. et al. Am. J. Cardiol. 17(Suppl.B):132B-136B, 1991), cyclosporin A (Jonasson, L. et al., Proc. Natl.,Acad. Sci., 85: 2303, 1988), goat-anti-rabbit PDGF antibody (Ferns, G.A. A., et al., Science 253: 1129-1132, 1991), terbinafine (Nemecek, G.M. et al., J. Pharmacol. Exp. Thera. 248: 1167-1174, 1989), trapidil(Liu, M. W. et al., Circ. 81: 1089-1093, 1990), tranilast (Fukuyama, J.et al., Eur. J. Pharmacol. 318: 327-332, 1996), interferon-gamma(Hansson, G. K. and Holm, J., Circ. 84: 1266-1272, 1991), rapamycin(Marx, S. O. et al., Circ. Res. 76: 412-417, 1995), steroids (Colburn,M. D. et al., J. Vasc. Surg. 15: 510-518, 1992), see also Berk, B. C. etal., J. Am. Coll. Cardiol. 17: 111B-117B, 1991), ionizing radiation(Weinberger, J. et al., Int. J. Rad. One. Biol. Phys. 36: 767-775,1996), fusion toxins (Farb, A. et al., Circ. Res. 80: 542-550, 1997)antisense oligionucleotides (Simons, M. et al., Nature 359: 67-70, 1992)and gene vectors (Chang, M. W. et al., J. Clin. Invest. 96: 2260-2268,1995). Anti-proliferative action on smooth muscle cells in vitro hasbeen demonstrated for many of these agents, including heparin andheparin conjugates, taxol, tranilast, colchicine, ACE inhibitors, fusiontoxins, antisense oligionucleotides, rapamycin and ionizing radiation.Thus, agents with diverse mechanisms of smooth muscle cell inhibitionmay have therapeutic utility in reducing intimal hyperplasia.

However, in contrast to animal models, attempts in human angioplastypatients to prevent restenosis by systemic pharmacologic means have thusfar been unsuccessful. Neither aspirin-dipyridamole, ticlopidine,anti-coagulant therapy (acute heparin, chronic warfarin, hirudin orhirulog), thromboxane receptor antagonism nor steroids have beeneffective in preventing restenosis, although platelet inhibitors havebeen effective in preventing acute reocclusion after angioplasty (Makand Topol, 1997; Lang et al., 1991; Popma et al., 1991). The platelet GPII_(b)/III_(a) receptor, antagonist, Reopro® is still under study butReopro® has not shown definitive results for the reduction in restenosisfollowing angioplasty and stenting. Other agents, which have also beenunsuccessful in the prevention of restenosis, include the calciumchannel antagonists, prostacyclin mimetics, angiotensin convertingenzyme inhibitors, serotonin receptor antagonists, andanti-proliferative agents. These agents must be given systemically,however, and attainment of a therapeutically effective dose may not bepossible; anti-proliferative (or anti-restenosis) concentrations mayexceed the known toxic concentrations of these agents so that levelssufficient to produce smooth muscle inhibition may not be reached (Makand Topol, 1997; Lang et al., 1991; Popma et al., 1991).

Additional clinical trials in which the effectiveness for preventingrestenosis utilizing dietary fish oil supplements or cholesterollowering agents has been examined showing either conflicting or negativeresults so that no pharmacological agents are as yet clinicallyavailable to prevent post-angioplasty restenosis (Mak and Topol, 1997;Franklin and Faxon, 1993: Serruys, P. W. et al., 1993). Recentobservations suggest that the antilipid/antioxident agent, probucol, maybe useful in preventing restenosis but this work requires confirmation(Tardif et al., 1997; Yokoi, et al., 1997). Probucol is presently notapproved for use in the United States and a thirty-day pretreatmentperiod would preclude its use in emergency angioplasty. Additionally,the application of ionizing radiation has shown significant promise inreducing or preventing restenosis after angioplasty in patients withstents (Teirstein et al., 1997). Currently, however, the most effectivetreatments for restenosis are repeat angioplasty, atherectomy orcoronary artery bypass grafting, because no therapeutic agents currentlyhave Food and Drug Administration approval for use for the prevention ofpost-angioplasty restenosis.

Unlike systemic pharmacologic therapy, stents have proven useful insignificantly reducing restenosis. Typically, stents areballoon-expandable slotted metal tubes (usually, but not limited to,stainless steel), which, when expanded within the lumen of anangioplastied coronary artery, provide structural support through rigidscaffolding to the arterial wall. This support is helpful in maintainingvessel lumen patency. In two randomized clinical trials, stentsincreased angiographic success after percutaneous transluminal coronaryangioplasty, by increasing minimal lumen diameter and reducing, but noteliminating, the incidence of restenosis at six months (Serruys et al.,1994; Fischman et al., 1994).

Additionally, the heparin coating of stents appears to have the addedbenefit of producing a reduction in sub-acute thrombosis after stentimplantation (Serruys et al., 1996). Thus, sustained mechanicalexpansion of a stenosed coronary artery with a stent has been shown toprovide some measure of restenosis prevention, and the coating of stentswith heparin has demonstrated both the feasibility and the clinicalusefulness of delivering drugs locally, at the site of injured tissue.

As stated above, the use of heparin coated stents demonstrates thefeasibility and clinical usefulness of local drug delivery; however, themanner in which the particular drug or drug combination is affixed tothe local delivery device will play a role in the efficacy of this typeof treatment. For example, the processes and materials utilized to affixthe drug/drug combinations to the local delivery device should notinterfere with the operations of the drug/drug combinations. Inaddition, the processes and materials utilized should be biocompatibleand maintain the drug/drug combinations on the local device throughdelivery and over a given period of time. For example, removal of thedrug/drug combination during delivery of the local delivery device maypotentially cause failure of the device.

Accordingly, there exists a need for drug/drug combinations andassociated local delivery devices for the prevention and treatment ofvascular injury causing intimal thickening which is either biologicallyinduced, for example, atherosclerosis, or mechanically induced, forexample, through percutaneous transluminal coronary angioplasty. Inaddition, there exists a need for maintaining the drug/drug combinationson the local delivery device through delivery and positioning as well asensuring that the drug/drug combination is released in therapeuticdosages over a given period of time.

A variety of stent coatings and compositions have been proposed for theprevention and treatment of injury causing intimal thickening. Thecoatings may be capable themselves of reducing the stimulus the stentprovides to the injured lumen wall, thus reducing the tendency towardsthrombosis or restenosis. Alternately, the coating may deliver apharmaceutical/therapeutic agent or drug to the lumen that reducessmooth muscle tissue proliferation or restenosis. The mechanism fordelivery of the agent is through diffusion of the agent through either abulk polymer or through pores that are created in the polymer structure,or by erosion of a biodegradable coating.

Both bioabsorbable and biostable compositions have been reported ascoatings for stents. They generally have been polymeric coatings thateither encapsulate a pharmaceutical/therapeutic agent or drug, e.g.rapamycin, taxol etc., or bind such an agent to the surface, e.g.heparin-coated stents. These coatings are applied to the stent in anumber of ways, including, though not limited to, dip, spray, or spincoating processes.

One class of biostable materials that has been reported as coatings forstents is polyfluoro homopolymers. Polytetrafluoroethylene (PTFE)homopolymers have been used as implants for many years. Thesehomopolymers are not soluble in any solvent at reasonable temperaturesand therefore are difficult to coat onto small medical devices whilemaintaining important features of the devices (e.g. slots in stents).

Stents with coatings made from polyvinylidenefluoride homopolymers andcontaining pharmaceutical/therapeutic agents or drugs for release havebeen suggested. However, like most crystalline polyfluoro homopolymers,they are difficult to apply as high quality films onto surfaces withoutsubjecting them to relatively high temperatures that correspond to themelting temperature of the polymer.

It would be advantageous to develop coatings for implantable medicaldevices that will reduce thrombosis, restenosis, or other adversereactions, that may include, but do not require, the use ofpharmaceutical or therapeutic agents or drugs to achieve such affects,and that possess physical and mechanical properties effective for use insuch devices even when such coated devices are subjected to relativelylow maximum temperatures. It would also be advantageous to developimplantable medical devices in combination with various drugs, agentsand/or compounds which treat disease and minimize or substantiallyeliminate a living organisms' reaction to the implantation of themedical device. In certain circumstances, it may be advantageous todevelop implantable medical devices in combination with various drugs,agents and/or compounds which promote wound healing andendothelialization of the medical device.

It would also be advantageous to develop delivery devices that providefor the delivery of the coated implantable medical devices withoutadversely affecting the coating or the medical device itself. Inaddition, such delivery devices should provide the physician with ameans for easily and accurately positioning the medical device in thetarget area.

It would also be advantageous to develop coatings for implantablemedical devices that allow for the precise control of the elution rateof drugs, agents and/or compounds from the implantable medical devices.

It would also be advantageous to develop delivery devices that providefor the release of one or more agents that act through differentmolecular mechanisms affecting cell proliferation.

It would also be advantageous to develop delivery devices that providefor the regional administration of one or more agents for the treatmentof atherosclerotic plaque.

It would also be advantageous to develop liquid formulations of thedrugs to increase the efficacy and deliverability thereof. Specifically,liquid solution dosage forms of water insoluble and lipophilic drugs aredifficult to create without resorting to substantial quantities ofsurfactants, co-solvents and the like.

Another type of vascular disease of considerable concern isatherosclerosis. Atherosclerosis is a thickening and hardening of thearteries and is generally believed to be caused by the progressivebuildup of fatty substances, e.g. cholesterol, inflammatory cells,cellular waste products, calcium and other substances in the innerlining or intima of the arteries. The buildup of these irritatingsubstances may in turn stimulate cells in the walls of the affectedarteries to produce additional substances that result in the furtherbuildup of cells leading to the growth of a lesion. This buildup orlesion is generally referred to as plaque.

Recent studies have lead to a shift in the understanding ofatherosclerosis and uncovered another major vascular problem not yetwell treated. Scientists theorize that at least some coronary disease isan inflammatory process, in which inflammation causes plaque todestabilize and rupture. This inflamed plaque is known asatherosclerotic vulnerable plaque.

Vulnerable plaque consists of a lipid-rich core covered by a thin layerof smooth muscle cells. These vulnerable plaques are prone to ruptureand erosion, and can cause significant infarcts if the thin cellularlayer ruptures or ulcerates. When the inflammatory cells erode orrupture, the lipid core is exposed to the blood flow, forming thrombi inthe artery. These thrombi may grow rapidly and block the artery, ordetach and travel downstream, leading to embolic events, unstableangina, myocardial infarction, and/or sudden death. In fact, some recentstudies have suggested that plaque rupture may trigger sixty to seventypercent of all fatal myocardial infarctions. See U.S. Pat. No. 5,924,997issued to Campbell and U.S. Pat. No. 6,245,026 issued to Campbell et al.for further descriptions of vulnerable plaques.

Early methods used to detect atherosclerosis lacked the diagnostic toolsto visualize and identify vulnerable plaque in cardiac patients.However, new diagnostic technologies are under development to identifythe location of vulnerable plaques in the coronary arteries. These newdevices include refined magnetic resonance imaging (MRI), thermalsensors that measure the temperature of the arterial wall on the premisethat the inflammatory process generates heat, elasticity sensors,intravascular ultrasound, optical coherence tomography (OCT), contrastagents, and near-infrared and infrared light. What is not currentlyclear, however, is how to treat these vulnerable plaque lesions oncethey are found.

Treating vulnerable plaque by using balloon angioplasty followed bytraditional stenting would provide less than satisfactory results.Balloon angioplasty by itself may rupture the vulnerable plaque exposingthe underlying fresh tissue cells, collagen or damaged endothelium, tothe blood flow. This condition ultimately leads to the formation of athrombi or blood clot that may partially or completely occlude thevessel. In addition, while bare or uncoated stents will induceneointimal hyperplasia that will provide a protective cover over thevulnerable plaque, restenosis remains a major problem that may createmore risk to the patient than the original vulnerable plaque.

Accordingly, it would be advantageous to develop a drug eluting stent orother medical device that effectively treats vulnerable plaque andrelated vascular disease.

One of the more common modes of drug degradation involves oxidation.Antioxidants are molecules that safely interact with free radicals andterminate the potential chain reaction caused by these highly reactiveradicals prior to vital molecule damage. In other words, antioxidantsare essentially scavengers that render free radicals inert prior todamaging molecules or portions of molecules. Accordingly, antioxidantsmay be utilized in drug formulations to prevent or substantially reducedrug degradation. More specifically, antioxidants may be added to oxygensensitive drug and/or drug/polymer solutions utilized to coat drugeluting implantable medical devices, such as stents, as well asinjectable drug solutions to prevent oxidation and reduce drugdegradation. A reduction in degradation due to oxidation will result inan extended shelf life of the drug or drug coated products.

Accordingly, it would be advantageous to develop a drug and antioxidantcombination that would substantially slow drug degradation.

It would also be advantageous to develop liquid formulations of thedrugs to increase the efficacy and deliverability thereof. Specifically,liquid solution and liquid suspension dosage forms of water insolubleand lipophilic drugs are difficult to create without resorting tosubstantial quantities of surfactants, co-solvents and the like.

SUMMARY OF THE INVENTION

The liquid formulations of a therapeutic agent in accordance with thepresent invention overcomes the disadvantages associated with the localor regional delivery of water insoluble and lipophilic drugs as brieflydescribed above.

In accordance with one aspect, the present invention is directed to aliquid formulation of a therapeutic agent comprising a taxane in apharmaceutically effective dosage and one or more pharmaceuticallyacceptable solubility enhancers.

In accordance with another aspect, the present invention is directed toa method for the treatment of vascular disease comprising theadministration of a liquid formulation of a taxane proximate the diseasesite.

In accordance with another aspect, the present invention is directed toan injectable formulation of a therapeutic agent comprising a taxane ina pharmaceutically effective dosage and one or more pharmaceuticallyacceptable solubility enhancers.

Various combinations of drugs, agents and/or compounds may be utilizedto treat various conditions. For example, rapamycin and trichostatin Amay be utilized to treat or prevent restenosis following vascularinjury. As rapamycin and trichostatin A act through different molecularmechanisms affecting cell proliferation, it is possible that theseagents, when combined on a drug eluting stent, may potentiate eachother's anti-restenotic activity by downregulating both smooth muscleand immune cell proliferation (inflammatory cell proliferation) bydistinct multiple mechanisms. This potentiation of sirolimusanti-proliferative activity by trichostatin A may translate to anenhancement in anti-restenotic efficacy following vascular injury duringrevascularization and other vascular surgical procedures and a reductionin the required amount of either agent to achieve the anti-restenoticeffect.

Trichostatin A may block neointimal formation by local vascularapplication (e.g. via stent- or catheter-based delivery) by virtue ofcomplete and potent blockade of human coronary artery smooth muscle cellproliferation. The combination of sirolimus and trichostatin A (andother agents within its pharmacologic class) represent a new therapeuticcombination that may be more efficacious against restenosis/neointimalthickening than rapamycin alone. Different doses of the combination maylead to additional gains of inhibition of the neointimal growth than thesimple additive effects of rapamycin plus trichostatin A. Thecombination of rapamycin and trichostatin A may be efficacious towardsother cardiovascular diseases such as vulnerable atherosclerotic plaque.

In an alternate exemplary embodiment, rapamycin may be utilized incombination with mycophenolic acid. As rapamycin and mycophenolic acidact through different molecular mechanisms affecting cell proliferationat different phases of the cell cycle, it is possible that these agents,when combined on a drug eluting stent or any other medical device asdefined herein, my potentiate each others anti-restenotic activity bydown regulating both smooth muscle and immune cell proliferation bydifferent mechanisms.

In yet another alternate exemplary embodiment, rapamycin may be utilizedin combination with cladribine. As rapamycin and cladribine act throughdifferent molecular mechanisms affecting cell proliferation at differentphases of the cell cycle, it is possible that these agents, whencombined on a drug eluting stent or any other medical device as definedherein, may potentiate each others anti-restenotic activity by downregulating both smooth muscle and immune cell proliferation by differentmechanisms. Essentially, the combination of rapamycin and cladribinerepresents a therapeutic combination that may be more efficacious thaneither agent alone or the simple sum of the effects of the two agents.In addition, different doses of the combination may lead to additionalgains of inhibition of the neointimal growth than rapamycin orcladribine alone.

In yet still another alternate exemplary embodiment, rapamycin may beutilized in combination with topotecan or other topoisomerase Iinhibitors, including irinotecan, camptothecin, camptosar and DX-8951f.As rapamycin and topotecan act through different molecular mechanismsaffecting cell proliferation at different phases of the cell cycle, itis possible that these agents, when combined on a drug eluting stent orany other medical device as defined herein, may potentiate each other'santi-restenotic activity by downregulating both smooth muscle cell andimmune cell proliferation (inflammatory cell proliferation) by distinctmultiple mechanisms. Essentially, the combination of rapamycin andtopotecan or other topoisomerase I inhibitors represents a therapeuticcombination that may be more efficacious than either agent alone or thesimple sum of the two agents. In addition, different doses of thecombination may lead to additional gains of inhibition of the neointimalgrowth than rapamycin or topotecan alone.

In yet still another alternate exemplary embodiment, rapamycin may beutilized in combination with etoposide or other cytostatic glucosides,including podophyllotoxin and its derivatives and teniposide. Asrapamycin and etoposide act through different molecular mechanismsaffecting cell proliferation at different phases of the cell cycle, itis possible that these agents, when combined on a drug eluting stent orany other medical device as defined herein, may potentiate each other'santi-restenotic activity by downregulating both smooth muscle cell andimmune cell proliferation (inflammatory cell proliferation) by distinctmultiple mechanisms. Essentially, the combination of rapamycin andetoposide or other cytostatic glucosides, including podophyllotoxin andits derivatives and teniposide, represents a therapeutic combinationthat may be more efficacious than either agent alone or the simple sumof the two agents. In addition, different doses of the combination maylead to additional gains of inhibition of the neointimal growth thanrapamycin or etoposide alone.

In yet still another alternate exemplary embodiment, 2-methoxyestradiolor Panzem® may be utilized alone or in combination with rapamycin toprevent restenosis following vascular injury. As rapamycin or sirolimusand Panzem® act to inhibit cell proliferation through differentmolecular mechanisms, it is possible that these agents, when combined ona drug eluting stent or any other medical device as described herein,may potentiate each other's anti-restenotic activity by downregulatingboth smooth muscle and immune cell proliferation by distinct multiplemechanisms. Essentially, the combination of rapamycin and Panzem® orother estrogen receptor modulators, represents a therapeutic combinationthat may be more efficacious than either agent alone or the simple sumof the two agents. In addition, different doses of the combination maylead to additional gains of inhibition of the neointimal growth thanrapamycin or Panzem® alone.

The medical devices, drug coatings, delivery devices and methods formaintaining the drug coatings or vehicles thereon of the presentinvention utilizes a combination of materials to treat disease, andreactions by living organisms due to the implantation of medical devicesfor the treatment of disease or other conditions. The local delivery ofdrugs, agents or compounds generally substantially reduces the potentialtoxicity of the drugs, agents or compounds when compared to systemicdelivery while increasing their efficacy.

Drugs, agents or compounds may be affixed to any number of medicaldevices to treat various diseases. The drugs, agents or compounds mayalso be affixed to minimize or substantially eliminate the biologicalorganism's reaction to the introduction of the medical device utilizedto treat a separate condition. For example, stents may be introduced toopen coronary arteries or other body lumens such as biliary ducts. Theintroduction of these stents cause a smooth muscle cell proliferationeffect as well as inflammation. Accordingly, the stents may be coatedwith drugs, agents or compounds to combat these reactions. Anastomosisdevices, routinely utilized in certain types of surgery, may also causea smooth muscle cell proliferation effect as well as inflammation.Stent-grafts and systems utilizing stent-grafts, for example, aneurysmbypass systems may be coated with drugs, agents and/or compounds whichprevent adverse affects caused by the introduction of these devices aswell as to promote healing and incorporation. Therefore, the devices mayalso be coated with drugs, agents and/or compounds to combat thesereactions. In addition, devices such as aneurysm bypass systems may becoated with drugs, agents and/or compounds that promote would healingand endothelialization, thereby reducing the risk of endoleaks or othersimilar phenomena.

The drugs, agents or compounds will vary depending upon the type ofmedical device, the reaction to the introduction of the medical deviceand/or the disease sought to be treated. The type of coating or vehicleutilized to immobilize the drugs, agents or compounds to the medicaldevice may also vary depending on a number of factors, including thetype of medical device, the type of drug, agent or compound and the rateof release thereof.

In order to be effective, the drugs, agents or compounds shouldpreferably remain on the medical devices during delivery andimplantation. Accordingly, various coating techniques for creatingstrong bonds between the drugs, agents or compounds may be utilized. Inaddition, various materials may be utilized as surface modifications toprevent the drugs, agents or compounds from coming off prematurely.

Alternately, the delivery devices for the coated implantable medicaldevice may be modified to minimize the potential risk of damage to thecoating or the device itself. For example, various modifications tostent delivery devices may be made in order to reduce the frictionalforces associated with deploying self-expanding stents. Specifically,the delivery devices may be coated with various substances orincorporate features for reducing the forces acting upon specific areasof the coated stent.

The self-expanding stent delivery system of the present inventioncomprises a sheath coated with a layer of pyrolytic carbon or similarsubstance. The layer of pyrolytic carbon may be affixed to the innerlumen of the sheath in the region of the stent or along the entirelength of the sheath. The pyrolytic carbon is hard enough to prevent theself-expanding stent from becoming embedded in the softer polymericsheath. In addition, pyrolytic carbon is a lubricious material. Thesetwo properties reduce the change of damage to the stent duringdeployment, reduce the forces required for stent deployment, therebymaking it easier for the physician to accomplish placement, and providefor more accurate stent deployment.

The pyrolytic carbon may be directly affixed to the inner lumen of thesheath or to a substrate which is then affixed to the inner lumen of thesheath. A variety of known techniques may be utilized in themanufacturing process. Pyrolytic carbon is biocompatible and iscurrently utilized in a number of implantable medical devices. Thepyrolytic carbon layer is sufficiently thick to provide theabove-described features and thin enough to maintain the overall profileand flexibility of the delivery system.

The lubricious nature of the pyrolytic carbon is particularlyadvantageous with drug coated stents. The drug coatings and polymercontaining drugs, agents or compounds should preferably remain on thestent for best results. A lubricious coating on the sheath substantiallyreduces the risk of the drug or polymer from rubbing off duringdelivery.

The self-expanding stent delivery system of the present invention mayalso comprise a modified shaft. The modified shaft may include aplurality of elements which protrude from the shaft in the gaps betweenthe stent elements. These elements may significantly reduce the forcesacting upon the stent during deployment by preventing or substantiallyreducing the compression of the stent. Without the plurality ofelements, the stent may move and compress against a stop on the innershaft of the delivery system. Compression of the stent leads to higherdeployment forces. Accordingly, a shaft comprising a plurality ofelements eliminates or substantially reduces longitudinal movement ofthe stent, thereby eliminating or substantially reducing compression. Inaddition, the protruding elements distribute the total force acting uponthe stent over the plurality of elements so that there is less localizedstress on the stent and any coating thereon.

The composition for coating the surface of an implantable medical deviceof the present invention uses a combination of two chemically differentpolymers to achieve a coating that provides a chemical and physicalbarrier to drug release. This combination is durable, lubricious andprovides control over the elution rate of any drugs, agents, and/orcompounds contained in the coating.

Microneedles or other catheter-based delivery systems such as perfusionballoons may be utilized to deliver one or more drugs, agents and/orcompounds, including rapamycin, to the site of atherosclerotic plaque.This type of regional delivery may be utilized alone or in combinationwith an implantable medical device with the same or different drugsaffixed thereto. The one or more drugs, agents and/or compounds arepreferably delivered to the adventitial space proximate the lesion.

A locally or regionally delivered solution or suspension of a potenttherapeutic agent, such as rapamycin and/or paclitaxel, offers a numberof advantages over a systemically delivered agent or an agent deliveredvia an implantable medical device. For example, a relatively high tissueconcentration may be achieved by the direct deposition of thepharmaceutical agent in the arterial wall. Depending on the location ofthe deposition, a different drug concentration profile may be achievedthan through that of a drug eluting stent. In addition, with a locallyor regionally delivered solution, there is no need for a permanentlyimplanted device such as a stent, thereby eliminating the potential sideaffects associated therewith, such as inflammatory reaction and longterm tissue damage. It is, however, important to note that the locallyor regionally delivered solution may be utilized in combination withdrug eluting stents or other coated implantable medical devices. Anotheradvantage of solution or liquid formulations and/or suspensions lies inthe fact that the adjustment of the excipients in the liquid formulationwould readily change the drug distribution and retention profiles. Inaddition, the liquid formulation may be mixed immediately prior to theinjection through a pre-packaged multi-chamber injection device toimprove the storage and shelf life of the dosage forms.

Vulnerable plaque is a vascular disease wherein a lipid-rich core iscovered by a thin layer of smooth muscle cells. These vulnerable plaquesare prone to rupture and erosion, and can cause significant infarcts ifthe thin inflammatory cell layer ruptures or ulcerates. When theinflammatory cells erode or rupture, the lipid core is exposed to theblood flow, forming thrombi in the artery. These thrombi may growrapidly and block the artery, or detach and travel downstream, leadingto embolic events, unstable angina, myocardial infarction, and/or suddendeath. The present invention is directed to a scaffold structuredesigned to maintain vessel patency and which comprises a polymericcoating architecture including one or more therapeutic drugs, agentsand/or compounds for treating the inflammation and other disease statesassociated with vulnerable plaque rupture and lipid core metabolism.Anti-inflammatory therapeutic drugs, agents and/or compounds may beincorporated into the coating architecture for fast release to addressthe inflammatory acute phase of the disease and lipid lowering drugs,agents and/or compounds may be incorporated into the coatingarchitecture for slow release to address the chronic phase of thedisease. In addition, multiple drugs may be combined to provide asynergistic effect. The different drugs act through different mechanismsto act on different aspects of the disease.

One of the more common modes of drug degradation involves oxidation.Antioxidants are molecules that safely interact with free radicals andterminate the potential chain reaction caused by these highly reactiveradicals prior to vital molecule damage. In other words, antioxidantsare essentially scavengers that render free radicals inert prior todamaging molecules or portions of molecules. Accordingly, antioxidantsmay be utilized in drug formulations to prevent or substantially reducedrug degradation. More specifically, antioxidants may be added to oxygensensitive drug and/or drug/polymer solutions utilized to coat drugeluting implantable medical devices, such as stents, as well asinjectable drug solutions to prevent oxidation and reduce drugdegradation. A reduction in degradation due to oxidation will result inan extended shelf life of the drug or drug coated products.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following, more particular description of preferredembodiments of the invention, as illustrated in the accompanyingdrawings.

FIG. 1 is a view along the length of a stent (ends not shown) prior toexpansion showing the exterior surface of the stent and thecharacteristic banding pattern.

FIG. 2 is a perspective view along the length of the stent of FIG. 1having reservoirs in accordance with the present invention.

FIG. 3 indicates the fraction of drug released as a function of timefrom coatings of the present invention over which no topcoat has beendisposed.

FIG. 4 indicates the fraction of drug released as a function of timefrom coatings of the present invention including a topcoat disposedthereon.

FIG. 5 indicates the fraction of drug released as a function of timefrom coatings of the present invention over which no topcoat has beendisposed.

FIG. 6 indicates in vivo stent release kinetics of rapamycin frompoly(VDF/HFP).

FIG. 7 is a cross-sectional view of a band of the stent of FIG. 1 havingdrug coatings thereon in accordance with a first exemplary embodiment ofthe invention.

FIG. 8 is a cross-sectional view of a band of the stent of FIG. 1 havingdrug coatings thereon in accordance with a second exemplary embodimentof the invention.

FIG. 9 is a cross-sectional view of a band of the stent of FIG. 1 havingdrug coatings thereon in accordance with a third exemplary embodiment ofthe present invention.

FIGS. 10-13 illustrate an exemplary one-piece embodiment of ananastomosis device having a fastening flange and attached staple membersin accordance with the present invention.

FIG. 14 is a side view of an apparatus for joining anatomical structurestogether, according to an exemplary embodiment of the invention.

FIG. 15 is a cross-sectional view showing a needle portion of the FIG.14 apparatus passing through edges of anatomical structures, accordingto an exemplary embodiment of the invention.

FIG. 16 is a cross-sectional view showing the FIG. 14 apparatus pulledthrough an anastomosis, according to an exemplary embodiment of theinvention.

FIG. 17 is a cross-sectional view showing a staple of the FIG. 14apparatus being placed into proximity with the anatomical structures,according to an exemplary embodiment of the invention

FIG. 18 is a cross-sectional view showing a staple of the FIG. 14apparatus being engaged on both sides of the anastomosis, according toan exemplary embodiment of the invention.

FIG. 19 is a cross-sectional view showing a staple after it has beencrimped to join the anatomical structures, according to an exemplaryembodiment of the invention.

FIG. 20 is a cross-sectional view of a balloon having a lubriciouscoating affixed thereto in accordance with the present invention.

FIG. 21 is a cross-sectional view of a band of the stent in FIG. 1having a lubricious coating affixed thereto in accordance with thepresent invention.

FIG. 22 is a partial cross-sectional view of a self-expanding stent in adelivery device having a lubricious coating in accordance with thepresent invention.

FIG. 23 is a cross-sectional view of a band of the stent in FIG. 1having a modified polymer coating in accordance with the presentinvention.

FIG. 24 is a side elevation of an exemplary stent-graft in accordancewith the present invention.

FIG. 25 is a fragmentary cross-sectional view of another alternateexemplary embodiment of a stent-graft in accordance with the presentinvention.

FIG. 26 is a fragmentary cross-sectional view of another alternateexemplary embodiment of a stent-graft in accordance with the presentinvention.

FIG. 27 is an elevation view of a fully deployed aortic repair system inaccordance with the present invention.

FIG. 28 is a perspective view of a stent for a first prosthesis, shownfor clarity in an expanded state, in accordance with the presentinvention.

FIG. 29 is a perspective view of a first prosthesis having a stentcovered by a gasket material in accordance with the present invention.

FIG. 30 is a diagrammatic representation of an uncoated surgical staplein accordance with the present invention.

FIG. 31 is a diagrammatic representation of a surgical staple having amultiplicity of through-holes in accordance with the present invention.

FIG. 32 is a diagrammatic representation of a surgical staple having acoating on the outer surface thereof in accordance with the presentinvention.

FIG. 33 is a diagrammatic representation of a section of suture materialhaving a coating thereon in accordance with the present invention.

FIG. 34 is a diagrammatic representation of a section of suture materialhaving a coating impregnated into the surface thereof in accordance withthe present invention.

FIG. 35 is a simplified elevational view of a stent delivery apparatusmade in accordance with the present invention.

FIG. 36 is a view similar to that of FIG. 35 but showing an enlargedview of the distal end of the apparatus having a section cut away toshow the stent loaded therein.

FIG. 37 is a simplified elevational view of the distal end of the innershaft made in accordance with the present invention.

FIG. 38 is a cross-sectional view of FIG. 37 taken along lines 38-38.

FIGS. 39 through 43 are partial cross-sectional views of the apparatusof the present invention sequentially showing the deployment of theself-expanding stent within the vasculature.

FIG. 44 is a simplified elevational view of a shaft for a stent deliveryapparatus made in accordance with the present invention.

FIG. 45 is a partial cross-sectional view of the shaft and sheath of thestent delivery apparatus in accordance with the present invention.

FIG. 46 is a partial cross-sectional view of the shaft and modifiedsheath of the stent delivery system in accordance with the presentinvention.

FIG. 47 is a partial cross-sectional view of the shaft and modifiedsheath of the stent delivery system in accordance with the presentinvention.

FIG. 48 is a partial cross-sectional view of a modified shaft of thestent delivery system in accordance with the present invention.

FIG. 49 indicates the fraction or percentage of rapamycin released overtime from various polymeric coatings during in vivo testing inaccordance with the present invention.

FIG. 50 indicates the fraction or percentage of rapamycin released overtime from various polymeric coatings during in vitro testing inaccordance with the present invention.

FIG. 51 is a graphical representation of the inhibition of coronaryartery smooth muscle cell proliferation utilizing trichostatin A in anin vitro cell culture study.

FIG. 52 is a graphical representation of the anti-proliferative activityof rapamycin with varying concentrations of mycophenolic acid innon-synchronized cultured human coronary artery smooth muscle cellsstimulated with two percent fetal bovine serum in accordance with thepresent invention.

FIG. 53 is a graphical representation of the in vivo release kinetics ofrapamycin from a combination of rapamycin, mycophenolic acid and apolymer in porcine pharmacokinetics studies in accordance with thepresent invention.

FIG. 54 is a graphical representation of the in vivo release kinetics ofmycophenolic acid from a combination of rapamycin, mycophenolic acid anda polymer in porcine pharmacokinetics studies in accordance with thepresent invention.

FIG. 55 is a graphical representation of the in vitro release kineticsof rapamycin from a combination of rapamycin and mycophenolic acid inaccordance with the present invention.

FIG. 56 is a graphical representation of the in vivo release kinetics ofboth rapamycin and mycophenolic acid in porcine pharmacokinetics studiesin accordance with the present invention.

FIG. 57 is a graphical representation of the anti-proliferative activityof rapamycin with varying concentrations of cladribine innon-synchronized cultured human coronary artery smooth muscle cellsstimulated with two percent fetal bovine serum in accordance with thepresent invention.

FIG. 58 is a graphical representation of the anti-proliferative activityof cladribine in non-synchronized cultured human coronary artery smoothmuscle cells stimulated with two percent fetal bovine serum inaccordance with the present invention.

FIG. 59 is a graphical representation of the in vitro release kineticsof cladribine from non-sterile cladribine coatings in a PVDF/HFPbasecoat incorporated in a twenty-five percent ethanol/water releasemedium at room temperature in accordance with the present invention.

FIG. 60 is a graphical representation of the in vitro release kineticsof cladribine from sterile cladribine coatings in a PVDF/HFP basecoatincorporated in a twenty-five percent ethanol/water release medium atroom temperature in accordance with the present invention.

FIG. 61 is a graphical representation of the in vivo release kinetics ofcladribine from a polymeric coating in porcine pharmacokinetics studiesin accordance with the present invention.

FIG. 62 is a graphical representation of the in vivo release kinetics ofrapamycin from a combination of rapamycin, cladribine and a polymer inporcine pharmacokinetics studies in accordance with the presentinvention.

FIG. 63 is a graphical representation of the in vivo release kinetics ofcladribine from a combination of rapamycin, cladribine and a polymer inporcine pharmacokinetics studies in accordance with the presentinvention.

FIG. 64 is a graphical representation of the anti-proliferative activityof rapamycin with varying concentrations of topotecan in synchronizedcultured human coronary artery smooth muscle cells stimulated with twopercent fetal bovine serum in accordance with the present invention.

FIG. 65 is a graphical representation of the anti-proliferative activityof rapamycin with varying concentrations of etoposide in synchronizedcultured human coronary smooth muscle cells stimulated with two percentfetal bovine serum in accordance with the present invention.

FIG. 66 is a graphical representation of the anti-proliferative activityof Panzem® in synchronized cultured human coronary artery smooth musclecells stimulated with two percent fetal bovine serum in accordance withthe present invention.

FIG. 67 is a graphical representation of the anti-proliferative activityof rapamycin in synchronized cultured human coronary artery smoothmuscle cells stimulated with two percent fetal bovine serum inaccordance with the present invention.

FIG. 68 is a graphical representation of the anti-proliferative activityof rapamycin with varying concentrations of Panzem® in synchronizedcultured human coronary artery smooth muscle cells stimulated with twopercent fetal bovine serum in accordance with the present invention.

FIG. 69 is a graphical representation of a MTS assay of Panzem® inaccordance with the present invention.

FIG. 70 is a graphical representation of the in vitro release kineticsof rapamycin from a layered rapamycin, Panzem® and polymeric coating inaccordance with the present invention.

FIG. 71 is a graphical representation of the in vitro release kineticsof Panzem® from a layered rapamycin, Panzem® and polymeric coating inaccordance with the present invention.

FIG. 72A is a schematic, perspective view of a microfabricated surgicaldevice for interventional procedures in an unactuated condition inaccordance with the present invention.

FIG. 72B is a schematic view along line 72B-72B of FIG. 72A.

FIG. 72C is a schematic view along line 72C-72C of FIG. 72A.

FIG. 73A is a schematic, perspective view of a microfabricated surgicaldevice for interventional procedures in an actuated condition inaccordance with the present invention.

FIG. 73B is a schematic view along line 73B-73B of FIG. 73A.

FIG. 74 is a schematic, perspective view of the microfabricated surgicaldevice of the present invention inserted into a patient's vasculature.

FIG. 75 is a graphical representation of the results of a bioactivitystudy in accordance with the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The drug/drug combinations and delivery devices of the present inventionmay be utilized to effectively prevent and treat vascular disease, andin particular, vascular disease caused by injury. Various medicaltreatment devices utilized in the treatment of vascular disease mayultimately induce further complications. For example, balloonangioplasty is a procedure utilized to increase blood flow through anartery and is the predominant treatment for coronary vessel stenosis.However, as stated above, the procedure typically causes a certaindegree of damage to the vessel wall, thereby potentially exacerbatingthe problem at a point later in time. Although other procedures anddiseases may cause similar injury, exemplary embodiments of the presentinvention will be described with respect to the treatment of restenosisand related complications following percutaneous transluminal coronaryangioplasty and other similar arterial/venous procedures, including thejoining of arteries, veins and other fluid carrying conduits. Inaddition, various methods and devices will be described for theeffective delivery of the coated medical devices.

While exemplary embodiments of the invention will be described withrespect to the treatment of restenosis and related complicationsfollowing percutaneous transluminal coronary angioplasty, it isimportant to note that the local delivery of drug/drug combinations maybe utilized to treat a wide variety of conditions utilizing any numberof medical devices, or to enhance the function and/or life of thedevice. For example, intraocular lenses, placed to restore vision aftercataract surgery is often compromised by the formation of a secondarycataract. The latter is often a result of cellular overgrowth on thelens surface and can be potentially minimized by combining a drug ordrugs with the device. Other medical devices which often fail due totissue in-growth or accumulation of proteinaceous material in, on andaround the device, such as shunts for hydrocephalus, dialysis grafts,colostomy bag attachment devices, ear drainage tubes, leads for pacemakers and implantable defibrillators can also benefit from thedevice-drug combination approach. Devices which serve to improve thestructure and function of tissue or organ may also show benefits whencombined with the appropriate agent or agents. For example, improvedosteointegration of orthopedic devices to enhance stabilization of theimplanted device could potentially be achieved by combining it withagents such as bone-morphogenic protein. Similarly other surgicaldevices, sutures, staples, anastomosis devices, vertebral disks, bonepins, suture anchors, hemostatic barriers, clamps, screws, plates,clips, vascular implants, tissue adhesives and sealants, tissuescaffolds, various types of dressings, bone substitutes, intraluminaldevices, and vascular supports could also provide enhanced patientbenefit using this drug-device combination approach. Perivascular wrapsmay be particularly advantageous, alone or in combination with othermedical devices. The perivascular wraps may supply additional drugs to atreatment site. Essentially, any type of medical device may be coated insome fashion with a drug or drug combination which enhances treatmentover use of the singular use of the device or pharmaceutical agent.

In addition to various medical devices, the coatings on these devicesmay be used to deliver therapeutic and pharmaceutic agents including:anti-proliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas G(GP) II_(b)/III_(a) inhibitors and vitronectin receptor antagonists;anti-proliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);anti-proliferative/antimitotic antimetabolites such as folic acidanalogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine,and cytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);anti-coagulants (heparin, synthetic heparin salts and other inhibitorsof thrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);anti-inflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetaminophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF); angiotensin receptor blockers; nitric oxide donors;antisense oligionucleotides and combinations thereof; cell cycleinhibitors, mTOR inhibitors, and growth factor receptor signaltransduction kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMGco-enzyme reductase inhibitors (statins); and protease inhibitors.

As stated previously, the implantation of a coronary stent inconjunction with balloon angioplasty is highly effective in treatingacute vessel closure and may reduce the risk of restenosis.Intravascular ultrasound studies (Mintz et al., 1996) suggest thatcoronary stenting effectively prevents vessel constriction and that mostof the late luminal loss after stent implantation is due to plaquegrowth, probably related to neointimal hyperplasia. The late luminalloss after coronary stenting is almost two times higher than thatobserved after conventional balloon angioplasty. Thus, inasmuch asstents prevent at least a portion of the restenosis process, acombination of drugs, agents or compounds which prevents smooth musclecell proliferation, reduces inflammation and reduces coagulation orprevents smooth muscle cell proliferation by multiple mechanisms,reduces inflammation and reduces coagulation combined with a stent mayprovide the most efficacious treatment for post-angioplasty restenosis.The systemic use of drugs, agents or compounds in combination with thelocal delivery of the same or different drug/drug combinations may alsoprovide a beneficial treatment option.

The local delivery of drug/drug combinations from a stent has thefollowing advantages; namely, the prevention of vessel recoil andremodeling through the scaffolding action of the stent and theprevention of multiple components of neointimal hyperplasia orrestenosis as well as a reduction in inflammation and thrombosis. Thislocal administration of drugs, agents or compounds to stented coronaryarteries may also have additional therapeutic benefit. For example,higher tissue concentrations of the drugs, agents or compounds may beachieved utilizing local delivery, rather than systemic administration.In addition, reduced systemic toxicity may be achieved utilizing localdelivery rather than systemic administration while maintaining highertissue concentrations. Also in utilizing local delivery from a stentrather than systemic administration, a single procedure may suffice withbetter patient compliance. An additional benefit of combination drug,agent, and/or compound therapy may be to reduce the dose of each of thetherapeutic drugs, agents or compounds, thereby limiting their toxicity,while still achieving a reduction in restenosis, inflammation andthrombosis. Local stent-based therapy is therefore a means of improvingthe therapeutic ratio (efficacy/toxicity) of anti-restenosis,anti-inflammatory, anti-thrombotic drugs, agents or compounds.

There are a multiplicity of different stents that may be utilizedfollowing percutaneous transluminal coronary angioplasty. Although anynumber of stents may be utilized in accordance with the presentinvention, for simplicity, a limited number of stents will be describedin exemplary embodiments of the present invention. The skilled artisanwill recognize that any number of stents may be utilized in connectionwith the present invention. In addition, as stated above, other medicaldevices may be utilized.

A stent is commonly used as a tubular structure left inside the lumen ofa duct to relieve an obstruction. Commonly, stents are inserted into thelumen in a non-expanded form and are then expanded autonomously, or withthe aid of a second device in situ. A typical method of expansion occursthrough the use of a catheter-mounted angioplasty balloon which isinflated within the stenosed vessel or body passageway in order to shearand disrupt the obstructions associated with the wall components of thevessel and to obtain an enlarged lumen.

FIG. 1 illustrates an exemplary stent 100 which may be utilized inaccordance with an exemplary embodiment of the present invention. Theexpandable cylindrical stent 100 comprises a fenestrated structure forplacement in a blood vessel, duct or lumen to hold the vessel, duct orlumen open, more particularly for protecting a segment of artery fromrestenosis after angioplasty. The stent 100 may be expandedcircumferentially and maintained in an expanded configuration, that iscircumferentially or radially rigid. The stent 100 is axially flexibleand when flexed at a band, the stent 100 avoids any externallyprotruding component parts.

The stent 100 generally comprises first and second ends with anintermediate section therebetween. The stent 100 has a longitudinal axisand comprises a plurality of longitudinally disposed bands 102, whereineach band 102 defines a generally continuous wave along a line segmentparallel to the longitudinal axis. A plurality of circumferentiallyarranged links 104 maintain the bands 102 in a substantially tubularstructure. Essentially, each longitudinally disposed band 102 isconnected at a plurality of periodic locations, by a shortcircumferentially arranged link 104 to an adjacent band 102. The waveassociated with each of the bands 102 has approximately the samefundamental spatial frequency in the intermediate section, and the bands102 are so disposed that the wave associated with them are generallyaligned so as to be generally in phase with one another. As illustratedin the figure, each longitudinally arranged band 102 undulates throughapproximately two cycles before there is a link to an adjacent band 102.

The stent 100 may be fabricated utilizing any number of methods. Forexample, the stent 100 may be fabricated from a hollow or formedstainless steel tube that may be machined using lasers, electricdischarge milling, chemical etching or other means. The stent 100 isinserted into the body and placed at the desired site in an unexpandedform. In one exemplary embodiment, expansion may be effected in a bloodvessel by a balloon catheter, where the final diameter of the stent 100is a function of the diameter of the balloon catheter used.

It should be appreciated that a stent 100 in accordance with the presentinvention may be embodied in a shape-memory material, including, forexample, an appropriate alloy of nickel and titanium or stainless steel.Structures formed from stainless steel may be made self-expanding byconfiguring the stainless steel in a predetermined manner, for example,by twisting it into a braided configuration. In this embodiment afterthe stent 100 has been formed it may be compressed so as to occupy aspace sufficiently small as to permit its insertion in a blood vessel orother tissue by insertion means, wherein the insertion means include asuitable catheter, or flexible rod. On emerging from the catheter, thestent 100 may be configured to expand into the desired configurationwhere the expansion is automatic or triggered by a change in pressure,temperature or electrical stimulation.

FIG. 2 illustrates an exemplary embodiment of the present inventionutilizing the stent 100 illustrated in FIG. 1. As illustrated, the stent100 may be modified to comprise one or more reservoirs 106. Each of thereservoirs 106 may be opened or closed as desired. These reservoirs 106may be specifically designed to hold the drug/drug combinations to bedelivered. Regardless of the design of the stent 100, it is preferableto have the drug/drug combination dosage applied with enough specificityand a sufficient concentration to provide an effective dosage in thelesion area. In this regard, the reservoir size in the bands 102 ispreferably sized to adequately apply the drug/drug combination dosage atthe desired location and in the desired amount.

In an alternate exemplary embodiment, the entire inner and outer surfaceof the stent 100 may be coated with drug/drug combinations intherapeutic dosage amounts. A detailed description of a drug fortreating restenosis, as well as exemplary coating techniques, isdescribed below. It is, however, important to note that the coatingtechniques may vary depending on the drug/drug combinations. Also, thecoating techniques may vary depending on the material comprising thestent or other intraluminal medical device.

Rapamycin is a macrocyclic triene antibiotic produced by Streptomyceshygroscopicus as disclosed in U.S. Pat. No. 3,929,992. It has been foundthat rapamycin among other things inhibits the proliferation of vascularsmooth muscle cells in vivo. Accordingly, rapamycin may be utilized intreating intimal smooth muscle cell hyperplasia, restenosis, andvascular occlusion in a mammal, particularly following eitherbiologically or mechanically mediated vascular injury, or underconditions that would predispose a mammal to suffering such a vascularinjury. Rapamycin functions to inhibit smooth muscle cell proliferationand does not interfere with the re-endothelialization of the vesselwalls.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscleproliferation in response to mitogenic signals that are released duringan angioplasty induced injury. Inhibition of growth factor and cytokinemediated smooth muscle proliferation at the late G1 phase of the cellcycle is believed to be the dominant mechanism of action of rapamycin.However, rapamycin is also known to prevent T-cell proliferation anddifferentiation when administered systemically. This is the basis forits immunosuppressive activity and its ability to prevent graftrejection.

As used herein, rapamycin includes rapamycin and all analogs,derivatives and conjugates that bind to FKBP12, and other immunophilinsand possesses the same pharmacologic properties as rapamycin includinginhibition of TOR.

Although the anti-proliferative effects of rapamycin may be achievedthrough systemic use, superior results may be achieved through the localdelivery of the compound. Essentially, rapamycin works in the tissues,which are in proximity to the compound, and has diminished effect as thedistance from the delivery device increases. In order to take advantageof this effect, one would want the rapamycin in direct contact with thelumen walls. Accordingly, in a preferred embodiment, the rapamycin isincorporated onto the surface of the stent or portions thereof.Essentially, the rapamycin is preferably incorporated into the stent100, illustrated in FIG. 1, where the stent 100 makes contact with thelumen wall.

Rapamycin may be incorporated onto or affixed to the stent in a numberof ways. In the exemplary embodiment, the rapamycin is directlyincorporated into a polymeric matrix and sprayed onto the outer surfaceof the stent. The rapamycin elutes from the polymeric matrix over timeand enters the surrounding tissue. The rapamycin preferably remains onthe stent for at least three days up to approximately six months, andmore preferably between seven and thirty days.

Any number of non-erodible polymers may be utilized in conjunction withrapamycin. In one exemplary embodiment, the rapamycin or othertherapeutic agent may be incorporated into a film-forming polyfluorocopolymer comprising an amount of a first moiety selected from the groupconsisting of polymerized vinylidenefluoride and polymerizedtetrafluoroethylene, and an amount of a second moiety other than thefirst moiety and which is copolymerized with the first moiety, therebyproducing the polyfluoro copolymer, the second moiety being capable ofproviding toughness or elastomeric properties to the polyfluorocopolymer, wherein the relative amounts of the first moiety and thesecond moiety are effective to provide the coating and film producedtherefrom with properties effective for use in treating implantablemedical devices.

The present invention provides polymeric coatings comprising apolyfluoro copolymer and implantable medical devices, for example,stents coated with a film of the polymeric coating in amounts effectiveto reduce thrombosis and/or restenosis when such stents are used in, forexample, angioplasty procedures. As used herein, polyfluoro copolymersmeans those copolymers comprising an amount of a first moiety selectedfrom the group consisting of polymerized vinylidenefluoride andpolymerized tetrafluoroethylene, and an amount of a second moiety otherthan the first moiety and which is copolymerized with the first moietyto produce the polyfluoro copolymer, the second moiety being capable ofproviding toughness or elastomeric properties to the polyfluorocopolymer, wherein the relative amounts of the first moiety and thesecond moiety are effective to provide coatings and film made from suchpolyfluoro copolymers with properties effective for use in coatingimplantable medical devices.

The coatings may comprise pharmaceutical or therapeutic agents forreducing restenosis, inflammation, and/or thrombosis, and stents coatedwith such coatings may provide sustained release of the agents. Filmsprepared from certain polyfluoro copolymer coatings of the presentinvention provide the physical and mechanical properties required ofconventional coated medical devices, even where maximum temperature, towhich the device coatings and films are exposed, are limited torelatively low temperatures. This is particularly important when usingthe coating/film to deliver pharmaceutical/therapeutic agents or drugsthat are heat sensitive, or when applying the coating ontotemperature-sensitive devices such as catheters. When maximum exposuretemperature is not an issue, for example, where heat-stable agents suchas itraconazole are incorporated into the coatings, higher meltingthermoplastic polyfluoro copolymers may be used and, if very highelongation and adhesion is required, elastomers may be used. If desiredor required, the polyfluoro elastomers may be crosslinked by standardmethods described in, e.g., Modern Fluoropolymers, (J. Shires ed.), JohnWiley & Sons, New York, 1997, pp. 77-87.

The present invention comprises polyfluoro copolymers that provideimproved biocompatible coatings or vehicles for medical devices. Thesecoatings provide inert biocompatible surfaces to be in contact with bodytissue of a mammal, for example, a human, sufficient to reducerestenosis, or thrombosis, or other undesirable reactions. While manyreported coatings made from polyfluoro homopolymers are insoluble and/orrequire high heat, for example, greater than about one hundredtwenty-five degrees centigrade, to obtain films with adequate physicaland mechanical properties for use on implantable devices, for example,stents, or are not particularly tough or elastomeric, films preparedfrom the polyfluoro copolymers of the present invention provide adequateadhesion, toughness or elasticity, and resistance to cracking whenformed on medical devices. In certain exemplary embodiments, this is thecase even where the devices are subjected to relatively low maximumtemperatures.

The polyfluoro copolymers used for coatings according to the presentinvention are preferably film-forming polymers that have molecularweight high enough so as not to be waxy or tacky. The polymers and filmsformed therefrom should preferably adhere to the stent and not bereadily deformable after deposition on the stent as to be able to bedisplaced by hemodynamic stresses. The polymer molecular weight shouldpreferably be high enough to provide sufficient toughness so that filmscomprising the polymers will not be rubbed off during handling ordeployment of the stent. In certain exemplary embodiments the coatingwill not crack where expansion of the stent or other medical devicesoccurs.

Coatings of the present invention comprise polyfluoro copolymers, asdefined hereinabove. The second moiety polymerized with the first moietyto prepare the polyfluoro copolymer may be selected from thosepolymerized, biocompatible monomers that would provide biocompatiblepolymers acceptable for implantation in a mammal, while maintainingsufficient elastomeric film properties for use on medical devicesclaimed herein. Such monomers include, without limitation,hexafluoropropylene (HFP), tetrafluoroethylene (TFE),vinylidenefluoride, 1-hydropentafluoropropylene, perfluoro(methyl vinylether), chlorotrifluoroethylene (CTFE), pentafluoropropene,trifluoroethylene, hexafluoroacetone and hexafluoroisobutylene.

Polyfluoro copolymers used in the present invention typically comprisevinylidinefluoride copolymerized with hexafluoropropylene, in the weightratio in the range of from about fifty to about ninety-two weightpercent vinylidinefluoride to about fifty to about eight weight percentHFP. Preferably, polyfluoro copolymers used in the present inventioncomprise from about fifty to about eighty-five weight percentvinylidinefluoride copolymerized with from about fifty to about fifteenweight percent HFP. More preferably, the polyfluoro copolymers willcomprise from about fifty-five to about seventy weight percentvinylidinefluoride copolymerized with from about forty-five to aboutthirty weight percent HFP. Even more preferably, polyfluoro copolymerscomprise from about fifty-five to about sixty-five weight percentvinylidinefluoride copolymerized with from about forty-five to aboutthirty-five weight percent HFP. Such polyfluoro copolymers are soluble,in varying degrees, in solvents such as dimethylacetamide (DMAc),tetrahydrofuran, dimethyl formamide, dimethyl sulfoxide andn-methylpyrrolidone. Some are soluble in methylethylketone (MEK),acetone, methanol and other solvents commonly used in applying coatingsto conventional implantable medical devices.

Conventional polyfluoro homopolymers are crystalline and difficult toapply as high quality films onto metal surfaces without exposing thecoatings to relatively high temperatures that correspond to the meltingtemperature (Tm) of the polymer. The elevated temperature serves toprovide films prepared from such PVDF homopolymer coatings that exhibitsufficient adhesion of the film to the device, while preferablymaintaining sufficient flexibility to resist film cracking uponexpansion/contraction of the coated medical device. Certain films andcoatings according to the present invention provide these same physicaland mechanical properties, or essentially the same properties, even whenthe maximum temperatures to which the coatings and films are exposed isless than about a maximum predetermined temperature. This isparticularly important when the coatings/films comprise pharmaceuticalor therapeutic agents or drugs that are heat sensitive, for example,subject to chemical or physical degradation or other heat-inducednegative affects, or when coating heat sensitive substrates of medicaldevices, for example, subject to heat-induced compositional orstructural degradation.

Depending on the particular device upon which the coatings and films ofthe present invention are to be applied and the particular use/resultrequired of the device, polyfluoro copolymers used to prepare suchdevices may be crystalline, semi-crystalline or amorphous.

Where devices have no restrictions or limitations with respect toexposure of same to elevated temperatures, crystalline polyfluorocopolymers may be employed. Crystalline polyfluoro copolymers tend toresist the tendency to flow under applied stress or gravity when exposedto temperatures above their glass transition (Tg) temperatures.Crystalline polyfluoro copolymers provide tougher coatings and filmsthan their fully amorphous counterparts. In addition, crystallinepolymers are more lubricious and more easily handled through crimpingand transfer processes used to mount self-expanding stents, for example,nitinol stents.

Semi-crystalline and amorphous polyfluoro copolymers are advantageouswhere exposure to elevated temperatures is an issue, for example, whereheat-sensitive pharmaceutical or therapeutic agents are incorporatedinto the coatings and films, or where device design, structure and/oruse preclude exposure to such elevated temperatures. Semi-crystallinepolyfluoro copolymer elastomers comprising relatively high levels, forexample, from about thirty to about forty-five weight percent of thesecond moiety, for example, HFP, copolymerized with the first moiety,for example, VDF, have the advantage of reduced coefficient of frictionand self-blocking relative to amorphous polyfluoro copolymer elastomers.Such characteristics may be of significant value when processing,packaging and delivering medical devices coated with such polyfluorocopolymers. In addition, such polyfluoro copolymer elastomers comprisingsuch relatively high content of the second moiety serves to control thesolubility of certain agents, for example, rapamycin, in the polymer andtherefore controls permeability of the agent through the matrix.

Polyfluoro copolymers utilized in the present inventions may be preparedby various known polymerization methods. For example, high pressure,free-radical, semi-continuous emulsion polymerization techniques such asthose disclosed in Fluoroelastomers-dependence of relaxation phenomenaon compositions, POLYMER 30, 2180, 1989, by Ajroldi, et al., may beemployed to prepare amorphous polyfluoro copolymers, some of which maybe elastomers. In addition, free-radical batch emulsion polymerizationtechniques disclosed herein may be used to obtain polymers that aresemi-crystalline, even where relatively high levels of the second moietyare included.

As described above, stents may comprise a wide variety of materials anda wide variety of geometrics. Stents may be made of biocomptiblematerials, including biostable and bioabsorbable materials. Suitablebiocompatible metals include, but are not limited to, stainless steel,tantalum, titanium alloys (including nitinol), and cobalt alloys(including cobalt-chromium nickel alloys). Suitable nonmetallicbiocompatible materials include, but are not limited to, polyamides,polyolefins (i.e. polypropylene, polyethylene etc.), nonabsorbablepolyesters (i.e. polyethylene terephthalate), and bioabsorbablealiphatic polyesters (i.e. homopolymers and copolymers of lactic acid,glycolic acid, lactide, glycolide, para-dioxanone, trimethylenecarbonate, ε-caprolactone, and blends thereof).

The film-forming biocompatible polymer coatings generally are applied tothe stent in order to reduce local turbulence in blood flow through thestent, as well as adverse tissue reactions. The coatings and filmsformed therefrom also may be used to administer a pharmaceuticallyactive material to the site of the stent placement. Generally, theamount of polymer coating to be applied to the stent will vary dependingon, among other possible parameters, the particular polyfluoro copolymerused to prepare the coating, the stent design and the desired effect ofthe coating. Generally, the coated stent will comprise from about 0.1 toabout fifteen weight percent of the coating, preferably from about 0.4to about ten weight percent. The polyfluoro copolymer coatings may beapplied in one or more coating steps, depending on the amount ofpolyfluoro copolymer to be applied. Different polyfluoro copolymers maybe used for different layers in the stent coating. In fact, in certainexemplary embodiments, it is highly advantageous to use a diluted firstcoating solution comprising a polyfluoro copolymer as a primer topromote adhesion of a subsequent polyfluoro copolymer coating layer thatmay include pharmaceutically active materials. The individual coatingsmay be prepared from different polyfluoro copolymers.

Additionally, a top coating may be applied to delay release of thepharmaceutical agent, or they could be used as the matrix for thedelivery of a different pharmaceutically active material. Layering ofcoatings may be used to stage release of the drug or to control releaseof different agents placed in different layers.

Blends of polyfluoro copolymers may also be used to control the releaserate of different agents or to provide a desirable balance of coatingproperties, i.e. elasticity, toughness, etc., and drug deliverycharacteristics, for example, release profile. Polyfluoro copolymerswith different solubilities in solvents may be used to build updifferent polymer layers that may be used to deliver different drugs orto control the release profile of a drug. For example, polyfluorocopolymers comprising 85.5/14.5 (wt/wt) of poly(vinylidinefluoride/HFP)and 60.6/39.4 (wt/wt) of poly(vinylidinefluoride/HFP) are both solublein DMAc. However, only the 60.6/39.4 PVDF polyfluoro copolymer issoluble in methanol. So, a first layer of the 85.5/14.5 PVDF polyfluorocopolymer comprising a drug could be over coated with a topcoat of the60.6/39.4 PVDF polyfluoro copolymer made with the methanol solvent. Thetop coating may be used to delay the drug delivery of the drug containedin the first layer. Alternately, the second layer could comprise adifferent drug to provide for sequential drug delivery. Multiple layersof different drugs could be provided by alternating layers of first onepolyfluoro copolymer, then the other. As will be readily appreciated bythose skilled in the art, numerous layering approaches may be used toprovide the desired drug delivery.

Coatings may be formulated by mixing one or more therapeutic agents withthe coating polyfluoro copolymers in a coating mixture. The therapeuticagent may be present as a liquid, a finely divided solid, or any otherappropriate physical form. Optionally, the coating mixture may includeone or more additives, for example, nontoxic auxiliary substances suchas diluents, carriers, excipients, stabilizers or the like. Othersuitable additives may be formulated with the polymer andpharmaceutically active agent or compound. For example, a hydrophilicpolymer may be added to a biocompatible hydrophobic coating to modifythe release profile, or a hydrophobic polymer may be added to ahydrophilic coating to modify the release profile. One example would beadding a hydrophilic polymer selected from the group consisting ofpolyethylene oxide, polyvinyl pyrrolidone, polyethylene glycol,carboxylmethyl cellulose, and hydroxymethyl cellulose to a polyfluorocopolymer coating to modify the release profile. Appropriate relativeamounts may be determined by monitoring the in vitro and/or in vivorelease profiles for the therapeutic agents.

The best conditions for the coating application are when the polyfluorocopolymer and pharmaceutic agent have a common solvent. This provides awet coating that is a true solution. Less desirable, yet still usable,are coatings that contain the pharmaceutical agent as a solid dispersionin a solution of the polymer in solvent. Under the dispersionconditions, care must be taken to ensure that the particle size of thedispersed pharmaceutical powder, both the primary powder size and itsaggregates and agglomerates, is small enough not to cause an irregularcoating surface or to clog the slots of the stent that need to remainessentially free of coating. In cases where a dispersion is applied tothe stent and the smoothness of the coating film surface requiresimprovement, or to be ensured that all particles of the drug are fullyencapsulated in the polymer, or in cases where the release rate of thedrug is to be slowed, a clear (polyfluoro copolymer only) topcoat of thesame polyfluoro copolymer used to provide sustained release of the drugor another polyfluoro copolymer that further restricts the diffusion ofthe drug out of the coating may be applied. The topcoat may be appliedby dip coating with mandrel to clear the slots. This method is disclosedin U.S. Pat. No. 6,153,252. Other methods for applying the topcoatinclude spin coating and spray coating. Dip coating of the topcoat canbe problematic if the drug is very soluble in the coating solvent, whichswells the polyfluoro copolymer, and the clear coating solution acts asa zero concentration sink and redissolves previously deposited drug. Thetime spent in the dip bath may need to be limited so that the drug isnot extracted out into the drug-free bath. Drying should be rapid sothat the previously deposited drug does not completely diffuse into thetopcoat.

The amount of therapeutic agent will be dependent upon the particulardrug employed and medical condition being treated. Typically, the amountof drug represents about 0.001 percent to about seventy percent of thetotal coating weight, more typically about 0.001 percent to about sixtypercent of the total coating weight. It is possible that the drug mayrepresent as little as 0.0001 percent to the total coating weight.

The quantity and type of polyfluoro copolymers employed in the coatingfilm comprising the pharmaceutic agent will vary depending on therelease profile desired and the amount of drug employed. The product maycontain blends of the same or different polyfluoro copolymers havingdifferent molecular weights to provide the desired release profile orconsistency to a given formulation.

Polyfluoro copolymers may release dispersed drug by diffusion. This canresult in prolonged delivery (over, say approximately one totwo-thousand hours, preferably two to eight-hundred hours) of effectiveamounts (0.001 μg/cm²-min to 1000 μg/cm²-min) of the drug. The dosagemay be tailored to the subject being treated, the severity of theaffliction, the judgment of the prescribing physician, and the like.

Individual formulations of drugs and polyfluoro copolymers may be testedin appropriate in vitro and in vivo models to achieve the desired drugrelease profiles. For example, a drug could be formulated with apolyfluoro copolymer, or blend of polyfluoro copolymers, coated onto astent and placed in an agitated or circulating fluid system, forexample, twenty-five percent ethanol in water. Samples of thecirculating fluid could be taken to determine the release profile (suchas by HPLC, UV analysis or use of radiotagged molecules). The release ofa pharmaceutical compound from a stent coating into the interior wall ofa lumen could be modeled in appropriate animal system. The drug releaseprofile could then be monitored by appropriate means such as, by takingsamples at specific times and assaying the samples for drugconcentration (using HPLC to detect drug concentration). Thrombusformation can be modeled in animal models using the In-platelet imagingmethods described by Hanson and Harker, Proc. Natl. Acad. Sci. USA85:3184-3188 (1988). Following this or similar procedures, those skilledin the art will be able to formulate a variety of stent coatingformulations.

While not a requirement of the present invention, the coatings and filmsmay be crosslinked once applied to the medical devices. Crosslinking maybe affected by any of the known crosslinking mechanisms, such aschemical, heat or light. In addition, crosslinking initiators andpromoters may be used where applicable and appropriate. In thoseexemplary embodiments utilizing crosslinked films comprisingpharmaceutical agents, curing may affect the rate at which the drugdiffuses from the coating. Crosslinked polyfluoro copolymers films andcoatings of the present invention also may be used without drug tomodify the surface of implantable medical devices.

EXAMPLES Example 1

A PVDF homopolymer (Solef® 1008 from Solvay Advanced Polymers, Houston,Tex., Tm about 175° C.) and polyfluoro copolymers ofpoly(vinylidenefluoride/HFP), 92/8 and 91/9 weight percentvinylidenefluoride/HFP as determined by F¹⁹ NMR, respectively (eg:Solef® 11010 and 11008, Solvay Advanced Polymers, Houston, Tex., Tmabout 159 degrees C. and 160 degrees C., respectively) were examined aspotential coatings for stents. These polymers are soluble in solventssuch as, but not limited to, DMAc, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF) andacetone. Polymer coatings were prepared by dissolving the polymers inacetone, at five weight percent as a primer, or by dissolving thepolymer in 50/50 DMAc/acetone, at thirty weight percent as a topcoat.Coatings that were applied to the stents by dipping and dried at 60degrees C. in air for several hours, followed by 60 degrees C. for threehours in a <100 mm Hg vacuum, resulted in white foamy films. As applied,these films adhered poorly to the stent and flaked off, indicating theywere too brittle. When stents coated in this manner were heated above175 degrees C., i.e. above the melting temperature of the polymer, aclear, adherent film was formed. Since coatings require hightemperatures, for example, above the melting temperature of the polymer,to achieve high quality films. As mentioned above, the high temperatureheat treatment is unacceptable for the majority of drug compounds due totheir thermal sensitivity.

Example 2

A polyfluoro copolymer (Solef® 21508) comprising 85.5 weight percentvinylidenefluoride copolymerized with 14.5 weight percent HFP, asdetermined by F¹⁹ NMR, was evaluated. This copolymer is less crystallinethan the polyfluoro homopolymer and copolymers described in Example 1.It also has a lower melting point reported to be about 133 degrees C.Once again, a coating comprising about twenty weight percent of thepolyfluoro copolymer was applied from a polymer solution in 50/50DMAc/MEK. After drying (in air) at 60 degrees C. for several hours,followed by 60 degrees C. for three hours in a <100 mtorr Hg vacuum,clear adherent films were obtained. This eliminated the need for a hightemperature heat treatment to achieve high quality films. Coatings weresmoother and more adherent than those of Example 1. Some coated stentsthat underwent expansion show some degree of adhesion loss and “tenting”as the film pulls away from the metal. Where necessary, modification ofcoatings containing such copolymers may be made, e.g. by addition ofplasticizers or the like to the coating compositions. Films preparedfrom such coatings may be used to coat stents or other medical devices,particularly where those devices are not susceptible to expansion to thedegree of the stents.

The coating process above was repeated, this time with a coatingcomprising the 85.5/14.6 (wt/wt) (vinylidenefluoride/HFP) and aboutthirty weight percent of rapamycin (Wyeth-Ayerst Laboratories,Philadelphia, Pa.), based on total weight of coating solids. Clear filmsthat would occasionally crack or peel upon expansion of the coatedstents resulted. It is believed that inclusion of plasticizers and thelike in the coating composition will result in coatings and films foruse on stents and other medical devices that are not susceptible to suchcracking and peeling.

Example 3

Polyfluoro copolymers of still higher HFP content were then examined.This series of polymers were not semicrystalline, but rather aremarketed as elastomers. One such copolymer is Fluorel™ FC2261Q (fromDyneon, a 3M-Hoechst Enterprise, Oakdale, Minn.), a 60.6/39.4 (wt/wt)copolymer of vinylidenefluoride/HFP. Although this copolymer has a Tgwell below room temperature (Tg about minus twenty degrees C.) it is nottacky at room temperature or even at sixty degrees C. This polymer hasno detectable crystallinity when measured by Differential Scanningcalorimetry (DSC) or by wide angle X-ray diffraction. Films formed onstents as described above were non-tacky, clear, and expanded withoutincident when the stents were expanded.

The coating process above was repeated, this time with coatingscomprising the 60.6/39.4 (wt/wt) (vinylidenefluoride/HFP) and aboutnine, thirty and fifty weight percent of rapamycin (Wyeth-AyerstLaboratories, Philadelphia, Pa.), based on total weight of coatingsolids, respectively. Coatings comprising about nine and thirty weightpercent rapamycin provided white, adherent, tough films that expandedwithout incident on the stent. Inclusion of fifty percent drug, in thesame manner, resulted in some loss of adhesion upon expansion.

Changes in the comonomer composition of the polyfluoro copolymer alsocan affect the nature of the solid state coating, once dried. Forexample, the semicrystalline copolymer, Solef® 21508, containing 85.5percent vinylidenefluoride polymerized with 14.5 percent by weight HFPforms homogeneous solutions with about 30 percent rapamycin (drug weightdivided by total solids weight, for example, drug plus copolymer) inDMAc and 50/50 DMAc/MEK. When the film is dried (60 degrees C./16 hoursfollowed by 60 degrees C./3 hours in vacuum of 100 mm Hg) a clearcoating, indicating a solid solution of the drug in the polymer, isobtained. Conversely, when an amorphous copolymer, Fluorel™ FC2261Q, ofPDVF/HFP at 60.6/39.5 (wt/wt) forms a similar thirty percent solution ofrapamycin in DMAc/MEK and is similarly dried, a white film, indicatingphase separation of the drug and the polymer, is obtained. This seconddrug containing film is much slower to release the drug into an in vitrotest solution of twenty-five percent ethanol in water than is the formerclear film of crystalline Solef® 21508. X-ray analysis of both filmsindicates that the drug is present in a non-crystalline form. Poor orvery low solubility of the drug in the high HFP containing copolymerresults in slow permeation of the drug through the thin coating film.Permeability is the product of diffusion rate of the diffusing species(in this case the drug) through the film (the copolymer) and thesolubility of the drug in the film.

Example 4 In Vitro Release Results of Rapamycin from Coating

FIG. 3 is a plot of data for the 85.5/14.5 vinylidenefluoride/HFPpolyfluoro copolymer, indicating fraction of drug released as a functionof time, with no topcoat. FIG. 4 is a plot of data for the samepolyfluoro copolymer over which a topcoat has been disposed, indicatingthat most effect on release rate is with a clear topcoat. As showntherein, TC150 refers to a device comprising one hundred fiftymicrograms of topcoat, TC235 refers to two hundred thirty-fivemicrograms of topcoat, etc. The stents before topcoating had an averageof seven hundred fifty micrograms of coating containing thirty percentrapamycin. FIG. 5 is a plot for the 60.6/39.4 vinylidenefluoride/HFPpolyfluoro copolymer, indicating fraction of drug released as a functionof time, showing significant control of release rate from the coatingwithout the use of a topcoat. Release is controlled by loading of drugin the film.

Example 5 In Vivo Stent Release Kinetics of Rapamycin from Poly(VDF/HFP)

Nine New Zealand white rabbits (2.5-3.0 kg) on a normal diet were givenaspirin twenty-four hours prior to surgery, again just prior to surgeryand for the remainder of the study. At the time of surgery, animals werepremedicated with Acepromazine (0.1-0.2 mg/kg) and anesthetized with aKetamine/Xylazine mixture (40 mg/kg and 5 mg/kg, respectively). Animalswere given a single intraprocedural dose of heparin (150 IU/kg, i.v.)

Arteriectomy of the right common carotid artery was performed and a 5 Fcatheter introducer (Cordis, Inc.) placed in the vessel and anchoredwith ligatures. Iodine contrast agent was injected to visualize theright common carotid artery, brachiocephalic trunk and aortic arch. Asteerable guide wire (0.014 inch/180 cm, Cordis, Inc.) was inserted viathe introducer and advanced sequentially into each iliac artery to alocation where the artery possesses a diameter closest to 2 mm using theangiographic mapping done previously. Two stents coated with a film madeof poly(VDF/HFP):(60.6/39.4) with thirty percent rapamycin were deployedin each animal where feasible, one in each iliac artery, using 3.0 mmballoon and inflation to 8-10 ATM for thirty seconds followed after aone minute interval by a second inflation to 8-10 ATM for thirtyseconds. Follow-up angiographs visualizing both iliac arteries areobtained to confirm correct deployment position of the stent.

At the end of procedure, the carotid artery was ligated and the skin isclosed with 3/0 vicryl suture using a one layered interrupted closure.Animals were given butoropanol (0.4 mg/kg, s.c.) and gentamycin (4mg/kg, i.m.). Following recovery, the animals were returned to theircages and allowed free access to food and water.

Due to early deaths and surgical difficulties, two animals were not usedin this analysis. Stented vessels were removed from the remaining sevenanimals at the following time points: one vessel (one animal) at tenminutes post implant; six vessels (three animals) between forty minutesand two hours post-implant (average, 1.2 hours); two vessels (twoanimals) at three days post implant; and two vessels (one animal) atseven days post-implant. In one animal at two hours, the stent wasretrieved from the aorta rather than the iliac artery. Upon removal,arteries were carefully trimmed at both the proximal and distal ends ofthe stent. Vessels were then carefully dissected free of the stent,flushed to remove any residual blood, and both stent and vessel frozenimmediately, wrapped separately in foil, labeled and kept frozen atminus eighty degrees C. When all samples had been collected, vessels andstents were frozen, transported and subsequently analyzed for rapamycinin tissue and results are illustrated in FIG. 4.

Example 6 Purifying the Polymer

The Fluorel™ FC2261Q copolymer was dissolved in MEK at about ten weightpercent and was washed in a 50/50 mixture of ethanol/water at a 14:1 ofethanol/water to MEK solution ratio. The polymer precipitated out andwas separated from the solvent phase by centrifugation. The polymeragain was dissolved in MEK and the washing procedure repeated. Thepolymer was dried after each washing step at sixty degrees C. in avacuum oven (<200 mtorr) over night.

Example 7 In Vivo Testing of Coated Stents in Porcine Coronary Arteries

CrossFlex® stents (available from Cordis, a Johnson & Johnson Company)were coated with the “as received” Fluorel™ FC2261Q PVDF copolymer andwith the purified polyfluoro copolymer of Example 6, using the dip andwipe approach. The coated stents were sterilized using ethylene oxideand a standard cycle. The coated stents and bare metal stents (controls)were implanted in porcine coronary arteries, where they remained fortwenty-eight days.

Angiography was performed on the pigs at implantation and attwenty-eight days. Angiography indicated that the control uncoated stentexhibited about twenty-one percent restenosis. The polyfluoro copolymer“as received” exhibited about twenty-six percent restenosis (equivalentto the control) and the washed copolymer exhibited about 12.5 percentrestenosis.

Histology results reported neointimal area at twenty-eight days to be2.89±0.2, 3.57±0.4 and 2.75±0.3, respectively, for the bare metalcontrol, the unpurified copolymer and the purified copolymer.

Since rapamycin acts by entering the surrounding tissue, it s preferablyonly affixed to the surface of the stent making contact with one tissue.Typically, only the outer surface of the stent makes contact with thetissue. Accordingly, in one exemplary embodiment, only the outer surfaceof the stent is coated with rapamycin.

The circulatory system, under normal conditions, has to be self-sealing,otherwise continued blood loss from an injury would be life threatening.Typically, all but the most catastrophic bleeding is rapidly stoppedthough a process known as hemostasis. Hemostasis occurs through aprogression of steps. At high rates of flow, hemostasis is a combinationof events involving platelet aggregation and fibrin formation. Plateletaggregation leads to a reduction in the blood flow due to the formationof a cellular plug while a cascade of biochemical steps leads to theformation of a fibrin clot.

Fibrin clots, as stated above, form in response to injury. There arecertain circumstances where blood clotting or clotting in a specificarea may pose a health risk. For example, during percutaneoustransluminal coronary angioplasty, the endothelial cells of the arterialwalls are typically injured, thereby exposing the sub-endothelial cells.Platelets adhere to these exposed cells. The aggregating platelets andthe damaged tissue initiate further biochemical process resulting inblood coagulation. Platelet and fibrin blood clots may prevent thenormal flow of blood to critical areas. Accordingly, there is a need tocontrol blood clotting in various medical procedures. Compounds that donot allow blood to clot are called anti-coagulants. Essentially, ananti-coagulant is an inhibitor of thrombin formation or function. Thesecompounds include drugs such as heparin and hirudin. As used herein,heparin includes all direct or indirect inhibitors of thrombin or FactorXa.

In addition to being an effective anti-coagulant, heparin has also beendemonstrated to inhibit smooth muscle cell growth in vivo. Thus, heparinmay be effectively utilized in conjunction with rapamycin in thetreatment of vascular disease. Essentially, the combination of rapamycinand heparin may inhibit smooth muscle cell growth via two differentmechanisms in addition to the heparin acting as an anti-coagulant.

Because of its multifunctional chemistry, heparin may be immobilized oraffixed to a stent in a number of ways. For example, heparin may beimmobilized onto a variety of surfaces by various methods, including thephotolink methods set forth in U.S. Pat. Nos. 3,959,078 and 4,722,906 toGuire et al. and U.S. Pat. Nos. 5,229,172; 5,308,641; 5,350,800 and5,415,938 to Cahalan et al. Heparinized surfaces have also been achievedby controlled release from a polymer matrix, for example, siliconerubber, as set forth in U.S. Pat. Nos. 5,837,313; 6,099,562 and6,120,536 to Ding et al.

Unlike rapamycin, heparin acts on circulating proteins in the blood andheparin need only make contact with blood to be effective. Accordingly,if used in conjunction with a medical device, such as a stent, it wouldpreferably be only on the side that comes into contact with the blood.For example, if heparin were to be administered via a stent, it wouldonly have to be on the inner surface of the stent to be effective.

In an exemplary embodiment of the invention, a stent may be utilized incombination with rapamycin and heparin to treat vascular disease. Inthis exemplary embodiment, the heparin is immobilized to the innersurface of the stent so that it is in contact with the blood and therapamycin is immobilized to the outer surface of the stent so that it isin contact with the surrounding tissue. FIG. 7 illustrates across-section of a band 102 of the stent 100 illustrated in FIG. 1. Asillustrated, the band 102 is coated with heparin 108 on its innersurface 110 and with rapamycin 112 on its outer surface 114.

In an alternate exemplary embodiment, the stent may comprise a heparinlayer immobilized on its inner surface, and rapamycin and heparin on itsouter surface. Utilizing current coating techniques, heparin tends toform a stronger bond with the surface it is immobilized to then doesrapamycin. Accordingly, it may be possible to first immobilize therapamycin to the outer surface of the stent and then immobilize a layerof heparin to the rapamycin layer. In this embodiment, the rapamycin maybe more securely affixed to the stent while still effectively elutingfrom its polymeric matrix, through the heparin and into the surroundingtissue. FIG. 8 illustrates a cross-section of a band 102 of the stent100 illustrated in FIG. 1. As illustrated, the band 102 is coated withheparin 108 on its inner surface 110 and with rapamycin 112 and heparin108 on its outer surface 114.

There are a number of possible ways to immobilize, i.e., entrapment orcovalent linkage with an erodible bond, the heparin layer to therapamycin layer. For example, heparin may be introduced into the toplayer of the polymeric matrix. In other embodiments, different forms ofheparin may be directly immobilized onto the top coat of the polymericmatrix, for example, as illustrated in FIG. 9. As illustrated, ahydrophobic heparin layer 116 may be immobilized onto the top coat layer118 of the rapamycin layer 112. A hydrophobic form of heparin isutilized because rapamycin and heparin coatings represent incompatiblecoating application technologies. Rapamycin is an organic solvent-basedcoating and heparin, in its native form, is a water-based coating.

As stated above, a rapamycin coating may be applied to stents by a dip,spray or spin coating method, and/or any combination of these methods.Various polymers may be utilized. For example, as described above,poly(ethylene-co-vinyl acetate) and polybutyl methacrylate blends may beutilized. Other polymers may also be utilized, but not limited to, forexample, polyvinylidene fluoride-co-hexafluoropropylene andpolyethylbutyl methacrylate-co-hexyl methacrylate. Also as describedabove, barrier or top coatings may also be applied to modulate thedissolution of rapamycin from the polymer matrix. In the exemplaryembodiment described above, a thin layer of heparin is applied to thesurface of the polymeric matrix. Because these polymer systems arehydrophobic and incompatible with the hydrophilic heparin, appropriatesurface modifications may be required.

The application of heparin to the surface of the polymeric matrix may beperformed in various ways and utilizing various biocompatible materials.For example, in one embodiment, in water or alcoholic solutions,polyethylene imine may be applied on the stents, with care not todegrade the rapamycin (e.g., pH<7, low temperature), followed by theapplication of sodium heparinate in aqueous or alcoholic solutions. Asan extension of this surface modification, covalent heparin may belinked on polyethylene imine using amide-type chemistry (using acarbondiimide activator, e.g. EDC) or reductive amination chemistry(using CBAS-heparin and sodium cyanoborohydride for coupling). Inanother exemplary embodiment, heparin may be photolinked on the surface,if it is appropriately grafted with photo initiator moieties. Uponapplication of this modified heparin formulation on the covalent stentsurface, light exposure causes cross-linking and immobilization of theheparin on the coating surface. In yet another exemplary embodiment,heparin may be complexed with hydrophobic quaternary ammonium salts,rendering the molecule soluble in organic solvents (e.g. benzalkoniumheparinate, troidodecylmethylammonium heparinate). Such a formulation ofheparin may be compatible with the hydrophobic rapamycin coating, andmay be applied directly on the coating surface, or in therapamycin/hydrophobic polymer formulation.

It is important to note that the stent, as described above, may beformed from any number of materials, including various metals, polymericmaterials and ceramic materials. Accordingly, various technologies maybe utilized to immobilize the various drugs, agent, compoundcombinations thereon. Specifically, in addition to the polymericmatricies described above biopolymers may be utilized. Biopolymers maybe generally classified as natural polymers, while the above-describedpolymers may be described as synthetic polymers. Exemplary biopolymers,which may be utilized include, agarose, alginate, gelatin, collagen andelastin. In addition, the drugs, agents or compounds may be utilized inconjunction with other percutaneously delivered medical devices such asgrafts and profusion balloons.

In addition to utilizing an anti-proliferative and anti-coagulant,anti-inflammatories may also be utilized in combination therewith. Oneexample of such a combination would be the addition of ananti-inflammatory corticosteroid such as dexamethasone with ananti-proliferative, such as rapamycin, cladribine, vincristine, taxol,or a nitric oxide donor and an anti-coagulant, such as heparin. Suchcombination therapies might result in a better therapeutic effect, i.e.,less proliferation as well as less inflammation, a stimulus forproliferation, than would occur with either agent alone. The delivery ofa stent comprising an anti-proliferative, anti-coagulant, and ananti-inflammatory to an injured vessel would provide the addedtherapeutic benefit of limiting the degree of local smooth muscle cellproliferation, reducing a stimulus for proliferation, i.e., inflammationand reducing the effects of coagulation thus enhancing therestenosis-limiting action of the stent.

In other exemplary embodiments of the inventions, growth factorinhibitor or cytokine signal transduction inhibitor, such as the rasinhibitor, R115777, or P38 kinase inhibitor, RWJ67657, or a tyrosinekinase inhibitor, such as tyrphostin, might be combined with ananti-proliferative agent such as taxol, vincristine or rapamycin so thatproliferation of smooth muscle cells could be inhibited by differentmechanisms. Alternatively, an anti-proliferative agent such as taxol,vincristine or rapamycin could be combined with an inhibitor ofextracellular matrix synthesis such as halofuginone. In the above cases,agents acting by different mechanisms could act synergistically toreduce smooth muscle cell proliferation and vascular hyperplasia. Thisinvention is also intended to cover other combinations of two or moresuch drug agents. As mentioned above, such drugs, agents or compoundscould be administered systemically, delivered locally via drug deliverycatheter, or formulated for delivery from the surface of a stent, orgiven as a combination of systemic and local therapy.

In addition to anti-proliferatives, anti-inflammatories andanti-coagulants, other drugs, agents or compounds may be utilized inconjunction with the medical devices. For example, immunosuppressantsmay be utilized alone or in combination with these other drugs, agentsor compounds. Also gene therapy delivery mechanisms such as modifiedgenes (nucleic acids including recombinant DNA) in viral vectors andnon-viral gene vectors such as plasmids may also be introduced locallyvia a medical device. In addition, the present invention may be utilizedwith cell based therapy.

In addition to all of the drugs, agents, compounds and modified genesdescribed above, chemical agents that are not ordinarily therapeuticallyor biologically active may also be utilized in conjunction with thepresent invention. These chemical agents, commonly referred to aspro-drugs, are agents that become biologically active upon theirintroduction into the living organism by one or more mechanisms. Thesemechanisms include the addition of compounds supplied by the organism orthe cleavage of compounds from the agents caused by another agentsupplied by the organism. Typically, pro-drugs are more absorbable bythe organism. In addition, pro-drugs may also provide some additionalmeasure of time release.

As stated above, rapamycin may be utilized alone or in combination withone or more drugs, agents and/or compounds for the prevention ofrestenosis following vascular injury.

Histone proteins are part of cellular chromatin that aid in thepackaging of DNA and transcription of genes. Several histone proteinsexist, each expressing net positive charges capable of interacting withanionic DNA. These histone proteins form nucleosome subunits aroundwhich DNA is wound. Chemical modification of the histones throughacetylation/deacetylation by acetyltransferase and deacetylase enzymesas well as other post-translational modifications help regulate theshape of the histone proteins, and subsequently, the accessibility ofDNA to transcription enzymes. In resting cells, gene transcription is,at least in part, regulated by a balance of acetylation (transcriptionON) and deacetylation (transcription OFF) of histone proteins that bindto DNA. Therefore, affecting the balance between acetylation anddeacetylation can ultimately impact gene transcription, andsubsequently, cell proliferation as proliferative pathways depend to asignificant degree on gene transcription. Histone deacetylase are of twogeneral classes, RPd3-like and Hda1-like proteins.

Other drugs, agents and or compounds that may be utilized include otherhistone deacetylase inhibitors, which include trichostatin A, itsanalogs and derivatives as well as similar agents. These agents includeshort-chain fatty acids, such as butyrate, phenylbutyrate and valproate,hydroxamic acids, such as trichostatins, SAHA and its derivatives,oxamflatin, ABHA, scriptaid, pyroxamide, and propenamides,epoxyketone-containing cyclic tetrapeptides, such as trapoxins,HC-toxin, chlamydocin, diheteropeptin, WF-3161 and Cyl-1 and Cyl-2,non-epoxyketone-containing cyclic tetrapeptides such as, FR901228 andapicidin, benzamides, such as MS-275 (MS-27-275), CI-994 and otherbenzamide analogs, and various miscellaneous structures, such asdepudecin and organosulfur compounds.

Trichostatin A is a histone deacetylase inhibitor that arrests tumorcell proliferation predominantly in the G1 and G2 phases of the cellcycle. The G1 and G2 phases of the cell cycle are the phasescharacterized by gene transcription. The anti-proliferative activity andpoint of cell cycle arrest profile of trichostatin A have beencharacterized primarily in tumor cell lines with anti-proliferativeIC50's in the low nM range (Woo et al., J. Med Chem, 45: 2877-2885,2002). In addition, trichostatin A has been shown to haveanti-angiogenic activity (Deroanne et al., Oncogene 21 (3): 427-436,2002).

In in vitro cell culture studies, trichostatin A has been shown tocompletely inhibit human coronary artery smooth muscle cellproliferation and has an anti-proliferative IC50 of approximately 6 nM.FIG. 51 is a graph of the inhibition of coronary artery smooth musclecells by trichostatin A in a cell culture study. It is thereforepossible that trichostatin A, delivered locally, may substantiallyinhibit neointimal formation following vascular injury.

Rapamycin, as described above, is a macroyclic triene antibioticproduced by streptomyces hygroscopicus as disclosed in U.S. Pat. No.3,929,992. It has been found that rapamycin inhibits the proliferationof vascular smooth muscle cells in vivo. Accordingly, rapamycin may beutilized in treating intimal smooth muscle cell hyperplasia, restenosisand vascular occlusion in a mammal, particularly following eitherbiologically or mechanically mediated vascular injury, or underconditions that would predispose a mammal to suffering such a vascularinjury. Rapamycin functions to inhibit smooth muscle cell proliferationand does not interfere with the re-endothelialization of the vesselwalls.

Rapamycin functions to inhibit smooth muscle cell proliferation througha number of mechanisms. In addition, rapamycin reduces the other effectscaused by vascular injury, for example, inflammation. The mechanisms ofaction and various functions of rapamycin are described in detail below.Rapamycin as used throughout this application shall include rapamycin,rapamycin analogs, derivatives and congeners that bind FKBP12 andpossess the same pharmacologic properties as rapamycin, as described indetail below.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscleproliferation in response to mitogenic signals that are released duringangioplasty. Inhibition of growth factor and cytokine mediated smoothmuscle proliferation at the late G1 phase of the cell cycle is believedto be the dominant mechanism of action of rapamycin. However, rapamycinis also known to prevent T-cell proliferation and differentiation whenadministered systemically. This is the basis for its immunosuppressiveactivity and its ability to prevent graft rejection.

The molecular events that are responsible for the actions of rapamycin,a known anti-proliferative, which acts to reduce the magnitude andduration of neointimal hyperplasia, are still being elucidated. It isknown, however, that rapamycin enters cells and binds to a high-affinitycytosolic protein called FKBP12. The complex of rapamycin and FKPB12 inturn binds to and inhibits a phosphoinositide (PI)-3 kinase called the“mammalian Target of Rapamycin” or TOR. TOR is a protein kinase thatplays a key role in mediating the downstream signaling events associatedwith mitogenic growth factors and cytokines in smooth muscle cells and Tlymphocytes. These events include phosphorylation of p27,phosphorylation of p70 s6 kinase and phosphorylation of 4BP-1, animportant regulator of protein translation.

It is recognized that rapamycin reduces restenosis by inhibitingneointimal hyperplasia. However, there is evidence that rapamycin mayalso inhibit the other major component of restenosis, namely, negativeremodeling. Remodeling is a process whose mechanism is not clearlyunderstood but which results in shrinkage of the external elastic laminaand reduction in lumenal area over time, generally a period ofapproximately three to six months in humans.

Negative or constrictive vascular remodeling may be quantifiedangiographically as the percent diameter stenosis at the lesion sitewhere there is no stent to obstruct the process. If late lumen loss isabolished in-lesion, it may be inferred that negative remodeling hasbeen inhibited. Another method of determining the degree of remodelinginvolves measuring in-lesion external elastic lamina area usingintravascular ultrasound (IVUS). Intravascular ultrasound is a techniquethat can image the external elastic lamina as well as the vascularlumen. Changes in the external elastic lamina proximal and distal to thestent from the post-procedural timepoint to four-month and twelve-monthfollow-ups are reflective of remodeling changes.

Evidence that rapamycin exerts an effect on remodeling comes from humanimplant studies with rapamycin coated stents showing a very low degreeof restenosis in-lesion as well as in-stent. In-lesion parameters areusually measured approximately five millimeters on either side of thestent i.e. proximal and distal. Since the stent is not present tocontrol remodeling in these zones which are still affected by balloonexpansion, it may be inferred that rapamycin is preventing vascularremodeling.

The data in Table 1 below illustrate that in-lesion percent diameterstenosis remains low in the rapamycin treated groups, even at twelvemonths. Accordingly, these results support the hypothesis that rapamycinreduces remodeling.

TABLE 1.0 Angiographic In-Lesion Percent Diameter Stenosis (%, mean ± SDand ″n = ″) In Patients Who Received a Rapamycin-Coated Stent CoatingPost 4-6 month 12 month Group Placement Follow Up Follow Up Brazil 10.6± 5.7 (30) 13.6 ± 8.6 (30) 22.3 ± 7.2 (15) Netherlands 14.7 ± 8.8 22.4 ±6.4 —

Additional evidence supporting a reduction in negative remodeling withrapamycin comes from intravascular ultrasound data that was obtainedfrom a first-in-man clinical program as illustrated in Table 2 below.

TABLE 2.0 Matched IVUS data in Patients Who Received a Rapamycin-CoatedStent 4-Month 12-Month Follow-Up Follow-Up IVUS Parameter Post (n=) (n=)(n=) Mean proximal vessel area 16.53 ± 3.53 16.31 ± 4.36 13.96 ± 2.26(mm²) (27) (28) (13) Mean distal vessel area 13.12 ± 3.68 13.53 ± 4.1712.49 ± 3.25 (mm²) (26) (26) (14)

The data illustrated that there is minimal loss of vessel areaproximally or distally which indicates that inhibition of negativeremodeling has occurred in vessels treated with rapamycin-coated stents.

Other than the stent itself, there have been no effective solutions tothe problem of vascular remodeling. Accordingly, rapamycin may representa biological approach to controlling the vascular remodeling phenomenon.

It may be hypothesized that rapamycin acts to reduce negative remodelingin several ways. By specifically blocking the proliferation offibroblasts in the vascular wall in response to injury, rapamycin mayreduce the formation of vascular scar tissue. Rapamycin may also affectthe translation of key proteins involved in collagen formation ormetabolism.

Rapamycin used in this context includes rapamycin and all analogs,derivatives and congeners that bind FKBP12 and possess the samepharmacologic properties as rapamycin.

In a preferred embodiment, the rapamycin is delivered by a localdelivery device to control negative remodeling of an arterial segmentafter balloon angioplasty as a means of reducing or preventingrestenosis. While any delivery device may be utilized, it is preferredthat the delivery device comprises a stent that includes a coating orsheath which elutes or releases rapamycin. The delivery system for sucha device may comprise a local infusion catheter that delivers rapamycinat a rate controlled by the administrator. In other embodiments, aninjection need may be utilized.

Rapamycin may also be delivered systemically using an oral dosage formor a chronic injectible depot form or a patch to deliver rapamycin for aperiod ranging from about seven to forty-five days to achieve vasculartissue levels that are sufficient to inhibit negative remodeling. Suchtreatment is to be used to reduce or prevent restenosis whenadministered several days prior to elective angioplasty with or withouta stent.

Data generated in porcine and rabbit models show that the release ofrapamycin into the vascular wall from a nonerodible polymeric stentcoating in a range of doses (35-430 ug/15-18 mm coronary stent) producesa peak fifty to fifty-five percent reduction in neointimal hyperplasiaas set forth in Table 3 below. This reduction, which is maximal at abouttwenty-eight to thirty days, is typically not sustained in the range ofninety to one hundred eighty days in the porcine model as set forth inTable 4 below.

TABLE 3.0 Animal Studies with Rapamycin-coated stents. Values are mean ±Standard Error of Mean Neointimal Area % Change From Study DurationStent¹ Rapamycin N (mm²) Polyme Metal Porcine 98009 14 days Metal 8 2.04± 0.17 1X + rapamycin 153 μg 8  1.66 ± 0.17* −42% −19% 1X + TC300 +rapamycin 155 μg 8  1.51 ± 0.19* −47% −26% 99005 28 days Metal 10 2.29 ±0.21 9  3.91 ± 0.60** 1X + TC30 + rapamycin 130 μg 8 2.81 ± 0.34 +23%1X + TC100 + rapamycin 120 μg 9 2.62 ± 0.21 +14% 99006 28 days Metal 124.57 ± 0.46 EVA/BMA 3X 12 5.02 ± 0.62 +10% 1X + rapamycin 125 μg 11   2.84 ± 0.31* ** −43% −38% 3X + rapamycin 430 μg 12    3.06 ± 0.17* **−39% −33% 3X + rapamycin 157 μg 12    2.77 ± 0.41* ** −45% −39% 99011 28days Metal 11 3.09 ± 0.27 11 4.52 ± 0.37 1X + rapamycin 189 μg 14 3.05 ±0.35  −1% 3X + rapamycin/dex 182/363 μg 14 2.72 ± 0.71 −12% 99021 60days Metal 12 2.14 ± 0.25 1X + rapamycin 181 μg 12 2.95 ± 0.38 +38%99034 28 days Metal 8 5.24 ± 0.58 1X + rapamycin 186 μg 8  2.47 ± 0.33**−53% 3X + rapamycin/dex 185/369 μg 6  2.42 ± 0.64** −54% 20001 28 daysMetal 6 1.81 ± 0.09 1X + rapamycin 172 μg 5 1.66 ± 0.44  −8% 20007 30days Metal 9 2.94 ± 0.43 1XTC + rapamycin 155 μg 10  1.40 ± 0.11*  −52%*Rabbit 99019 28 days Metal 8 1.20 ± 0.07 EVA/BMA 1X 10 1.26 ± 0.16  +5%1X + rapamycin  64 μg 9 0.92 ± 0.14 −27% −23% 1X + rapamycin 196 μg 10   0.66 ± 0.12* ** −48% −45% 99020 28 days Metal 12 1.18 ± 0.10 EVA/BMA1X + rapamycin 197 μg 8 0.81 ± 0.16 −32% ¹Stent nomenclature: EVA/BMA1X, 2X, and 3X signifies approx. 500 μg, 1000 μg, and 1500 μg total mass(polymer + drug), respectively. TC, top coat of 30 μg, 100 μg, or 300μg; drug-free BMA; Biphasic; 2 × 1X layers of rapamycin in EVA/BMAseparated by a 100 μg drug-free BMA layer. ²0.25 mg/kg/d × 14 dpreceeded by a loading dose of 0.5 mg/kg/d × 3 d prior to stentimplantation. *p < 0.05 from EVA/BMA control. **p < 0.05 from Metal;^(#)Inflammation score: (0 = essentially no intimal involvement; 1 =<25% intima involved; 2 = ≧25% intima involved; 3 = >50% intimainvolved).

TABLE 4.0 180 day Porcine Study with Rapamycin-coated stents. Values aremean ± Standard Error of Mean Neointimal Area % Change From InflammationStudy Duration Stent¹ Rapamycin N (mm²) Polyme Metal Score # 20007  3days Metal 10 0.38 ± 0.06 1.05 ± 0.06 (ETP-2-002233-P) 1XTC + rapamycin155 μg 10 0.29 ± 0.03 −24% 1.08 ± 0.04 30 days Metal 9 2.94 ± 0.43 0.11± 0.08 1XTC + rapamycin 155 μg 10  1.40 ± 0.11*  −52%* 0.25 ± 0.10 90days Metal 10 3.45 ± 0.34 0.20 ± 0.08 1XTC + rapamycin 155 μg 10 3.03 ±0.29 −12% 0.80 ± 0.23 1X + rapamycin 171 μg 10 2.86 ± 0.35 −17% 0.60 ±0.23 180 days  Metal 10 3.65 ± 0.39 0.65 ± 0.21 1XTC + rapamycin 155 μg10 3.34 ± 0.31  −8% 1.50 ± 0.34 1X + rapamycin 171 μg 10 3.87 ± 0.28 +6% 1.68 ± 0.37

The release of rapamycin into the vascular wall of a human from anonerodible polymeric stent coating provides superior results withrespect to the magnitude and duration of the reduction in neointimalhyperplasia within the stent as compared to the vascular walls ofanimals as set forth above.

Humans implanted with a rapamycin coated stent comprising rapamycin inthe same dose range as studied in animal models using the same polymericmatrix, as described above, reveal a much more profound reduction inneointimal hyperplasia than observed in animal models, based on themagnitude and duration of reduction in neointima. The human clinicalresponse to rapamycin reveals essentially total abolition of neointimalhyperplasia inside the stent using both angiographic and intravascularultrasound measurements. These results are sustained for at least oneyear as set forth in Table 5 below.

TABLE 5.0 Patients Treated (N = 45 patients) with a Rapamycin-coatedStent Sirolimus FIM 95% Effectiveness Measures (N = 45 Patients, 45Lesions) Confidence Limit Procedure Success (QCA) 100.0% (45/45) [92.1%,100.0%] 4-month In-Stent Diameter Stenosis (%) Mean ± SD (N) 4.8% ± 6.1%(30) [2.6%, 7.0%] Range (min, max) (−8.2%, 14.9%) 6-month In-StentDiameter Stenosis (%) Mean ± SD (N) 8.9% ± 7.6% (13) [4.8%, 13.0%] Range(min, max) (−2.9%, 20.4%) 12-month In-Stent Diameter Stenosis (%) Mean ±SD (N) 8.9% ± 6.1% (15) [5.8%, 12.0%] Range (min, max) (−3.0%, 22.0%)4-month In-Stent Late Loss (mm) Mean ± SD (N) 0.00 ± 0.29 (30) [−0.10,0.10] Range (min, max) (−0.51, 0.45) 6-month In-Stent Late Loss (mm)Mean ± SD (N) 0.25 ± 0.27 (13) [0.10, 0.39] Range (min, max) (−0.51,0.91) 12-month In-Stent Late Loss (mm) Mean ± SD (N) 0.11 ± 0.36 (15)[−0.08, 0.29] Range (min, max) (−0.51, 0.82) 4-month Obstruction Volume(%) (IVUS) Mean ± SD (N) 10.48% ± 2.78% (28) [9.45%, 11.51%] Range (min,max) (4.60%, 16.35%) 6-month Obstruction Volume (%) (IVUS) Mean ± SD (N)7.22% ± 4.60% (13) [4.72%, 9.72%], Range (min, max) (3.82%, 19.88%)12-month Obstruction Volume (%) (IVUS) Mean ± SD (N) 2.11% ± 5.28% (15)[0.00%, 4.78%], Range (min, max) (0.00%, 19.89%) 6-month Target LesionRevascularization (TLR) 0.0% (0/30) [0.0%, 9.5%] 12-month Target LesionRevascularization (TLR) 0.0% (0/15) [0.0%, 18.1%] QCA = QuantitativeCoronary Angiography SD = Standard Deviation IVUS = IntravascularUltrasound

Rapamycin produces an unexpected benefit in humans when delivered from astent by causing a profound reduction in in-stent neointimal hyperplasiathat is sustained for at least one year. The magnitude and duration ofthis benefit in humans is not predicted from animal model data.Rapamycin used in this context includes rapamycin and all analogs,derivatives and congeners that bind FKBP12 and possess the samepharmacologic properties as rapamycin.

These results may be due to a number of factors. For example, thegreater effectiveness of rapamycin in humans is due to greatersensitivity of its mechanism(s) of action toward the pathophysiology ofhuman vascular lesions compared to the pathophysiology of animal modelsof angioplasty. In addition, the combination of the dose applied to thestent and the polymer coating that controls the release of the drug isimportant in the effectiveness of the drug.

As stated above, rapamycin reduces vascular hyperplasia by antagonizingsmooth muscle proliferation in response to mitogenic signals that arereleased during angioplasty injury. Also, it is known that rapamycinprevents T-cell proliferation and differentiation when administeredsystemically. It has also been determined that rapamycin exerts a localinflammatory effect in the vessel wall when administered from a stent inlow doses for a sustained period of time (approximately two to sixweeks). The local anti-inflammatory benefit is profound and unexpected.In combination with the smooth muscle anti-proliferative effect, thisdual mode of action of rapamycin may be responsible for its exceptionalefficacy.

Accordingly, rapamycin delivered from a local device platform, reducesneointimal hyperplasia by a combination of anti-inflammatory and smoothmuscle anti-proliferative effects. Rapamycin used in this context meansrapamycin and all analogs, derivatives and congeners that bind FKBP12and possess the same pharmacologic properties as rapamycin. Local deviceplatforms include stent coatings, stent sheaths, grafts and local druginfusion catheters or porous balloons or any other suitable means forthe in situ or local delivery of drugs, agents or compounds.

The anti-inflammatory effect of rapamycin is evident in data from anexperiment, illustrated in Table 6, in which rapamycin delivered from astent was compared with dexamethasone delivered from a stent.Dexamethasone, a potent steroidal anti-inflammatory agent, was used as areference standard. Although dexamethasone is able to reduceinflammation scores, rapamycin is far more effective than dexamethasonein reducing inflammation scores. In addition, rapamycin significantlyreduces neointimal hyperplasia, unlike dexamethasone.

TABLE 6.0 Group Rapamycin Neointimal Area % Area Inflammation Rap N=(mm²) Stenosis Score Uncoated 8 5.24 ± 1.65 54 ± 19 0.97 ± 1.00Dexamethasone 8 4.31 ± 3.02 45 ± 31 0.39 ± 0.24 (Dex) Rapamycin 7 2.47 ±0.94* 26 ± 10* 0.13 ± 0.19* (Rap) Rap + Dex 6 2.42 ± 1.58* 26 ± 18* 0.17± 0.30* *= significance level P < 0.05

Rapamycin has also been found to reduce cytokine levels in vasculartissue when delivered from a stent. The data in FIG. 1 illustrates thatrapamycin is highly effective in reducing monocyte chemotactic protein(MCP-1) levels in the vascular wall. MCP-1 is an example of aproinflammatory/chemotactic cytokine that is elaborated during vesselinjury. Reduction in MCP-1 illustrates the beneficial effect ofrapamycin in reducing the expression of proinflammatory mediators andcontributing to the anti-inflammatory effect of rapamycin deliveredlocally from a stent. It is recognized that vascular inflammation inresponse to injury is a major contributor to the development ofneointimal hyperplasia.

Since rapamycin may be shown to inhibit local inflammatory events in thevessel it is believed that this could explain the unexpected superiorityof rapamycin in inhibiting neointima.

As set forth above, rapamycin functions on a number of levels to producesuch desired effects as the prevention of T-cell proliferation, theinhibition of negative remodeling, the reduction of inflammation, andthe prevention of smooth muscle cell proliferation. While the exactmechanisms of these functions are not completely known, the mechanismsthat have been identified may be expanded upon.

Studies with rapamycin suggest that the prevention of smooth muscle cellproliferation by blockade of the cell cycle is a valid strategy forreducing neointimal hyperplasia. Dramatic and sustained reductions inlate lumen loss and neointimal plaque volume have been observed inpatients receiving rapamycin delivered locally from a stent. The presentinvention expands upon the mechanism of rapamycin to include additionalapproaches to inhibit the cell cycle and reduce neointimal hyperplasiawithout producing toxicity.

The cell cycle is a tightly controlled biochemical cascade of eventsthat regulate the process of cell replication. When cells are stimulatedby appropriate growth factors, they move from G₀ (quiescence) to the G1phase of the cell cycle. Selective inhibition of the cell cycle in theG1 phase, prior to DNA replication (S phase), may offer therapeuticadvantages of cell preservation and viability while retaininganti-proliferative efficacy when compared to therapeutics that act laterin the cell cycle i.e. at S, G2 or M phase.

Accordingly, the prevention of intimal hyperplasia in blood vessels andother conduit vessels in the body may be achieved using cell cycleinhibitors that act selectively at the G1 phase of the cell cycle. Theseinhibitors of the G1 phase of the cell cycle may be small molecules,peptides, proteins, oligonucleotides or DNA sequences. Morespecifically, these drugs or agents include inhibitors of cyclindependent kinases (cdk's) involved with the progression of the cellcycle through the G1 phase, in particular cdk2 and cdk4.

Examples of drugs, agents or compounds that act selectively at the G1phase of the cell cycle include small molecules such as flavopiridol andits structural analogs that have been found to inhibit cell cycle in thelate G1 phase by antagonism of cyclin dependent kinases. Therapeuticagents that elevate an endogenous kinase inhibitory protein called P27,sometimes referred to as P27^(kip1), that selectively inhibits cyclindependent kinases may be utilized. This includes small molecules,peptides and proteins that either block the degradation of P27 orenhance the cellular production of P27, including gene vectors that cantransfact the gene to produce P27. Staurosporin and related smallmolecules that block the cell cycle by inhibiting protein kinases may beutilized. Protein kinase inhibitors, including the class of tyrphostinsthat selectively inhibit protein kinases to antagonize signaltransduction in smooth muscle in response to a broad range of growthfactors such as PDGF and FGF may also be utilized.

Any of the drugs, agents or compounds discussed above may beadministered either systemically, for example, orally, intravenously,intramuscularly, subcutaneously, nasally or intradermally, or locally,for example, stent coating, stent covering or local delivery catheter.In addition, the drugs or agents discussed above may be formulated forfast-release or slow release with the objective of maintaining the drugsor agents in contact with target tissues for a period ranging from threedays to eight weeks.

As set forth above, the complex of rapamycin and FKPB12 binds to andinhibits a phosphoinositide (PI)-3 kinase called the mammalian Target ofRapamycin or TOR. An antagonist of the catalytic activity of TOR,functioning as either an active site inhibitor or as an allostericmodulator, i.e. an indirect inhibitor that allosterically modulates,would mimic the actions of rapamycin but bypass the requirement forFKBP12. The potential advantages of a direct inhibitor of TOR includebetter tissue penetration and better physical/chemical stability. Inaddition, other potential advantages include greater selectivity andspecificity of action due to the specificity of an antagonist for one ofmultiple isoforms of TOR that may exist in different tissues, and apotentially different spectrum of downstream effects leading to greaterdrug efficacy and/or safety.

The inhibitor may be a small organic molecule (approximate mw<1000),which is either a synthetic or naturally derived product. Wortmanin maybe an agent which inhibits the function of this class of proteins. Itmay also be a peptide or an oligonucleotide sequence. The inhibitor maybe administered either sytemically (orally, intravenously,intramuscularly, subcutaneously, nasally, or intradermally) or locally(stent coating, stent covering, local drug delivery catheter). Forexample, the inhibitor may be released into the vascular wall of a humanfrom a nonerodible polymeric stent coating. In addition, the inhibitormay be formulated for fast-release or slow release with the objective ofmaintaining the rapamycin or other drug, agent or compound in contactwith target tissues for a period ranging from three days to eight weeks.

As stated previously, the implantation of a coronary stent inconjunction with balloon angioplasty is highly effective in treatingacute vessel closure and may reduce the risk of restenosis.Intravascular ultrasound studies (Mintz et al., 1996) suggest thatcoronary stenting effectively prevents vessel constriction and that mostof the late luminal loss after stent implantation is due to plaquegrowth, probably related to neointimal hyperplasia. The late luminalloss after coronary stenting is almost two times higher than thatobserved after conventional balloon angioplasty. Thus, inasmuch asstents prevent at least a portion of the restenosis process, the use ofdrugs, agents or compounds which prevent inflammation and proliferation,or prevent proliferation by multiple mechanisms, combined with a stentmay provide the most efficacious treatment for post-angioplastyrestenosis.

Further, insulin supplemented diabetic patients receiving rapamycineluting vascular devices, such as stents, may exhibit a higher incidenceof restenosis than their normal or non-insulin supplemented diabeticcounterparts. Accordingly, combinations of drugs may be beneficial.

The local delivery of drugs, agents or compounds from a stent has thefollowing advantages; namely, the prevention of vessel recoil andremodeling through the scaffolding action of the stent and the drugs,agents or compounds and the prevention of multiple components ofneointimal hyperplasia. This local administration of drugs, agents orcompounds to stented coronary arteries may also have additionaltherapeutic benefit. For example, higher tissue concentrations would beachievable than that which would occur with systemic administration,reduced systemic toxicity, and single treatment and ease ofadministration. An additional benefit of drug therapy may be to reducethe dose of the therapeutic compounds, thereby limiting their toxicity,while still achieving a reduction in restenosis.

As rapamycin and trichostatin A act through different molecularmechanisms affecting cell proliferation, it is possible that theseagents, when combined on a medical device such as a drug eluting stent,may potentiate each other's anti-restenotic activity by downregulatingboth smooth muscle and immune cell proliferation (inflammatory cellproliferation) by distinct multiple mechanisms. This potentiation ofrapamycin anti-proliferative activity by trichostatin A may translate toan enhancement in anti-restenotic efficacy following vascular injuryduring revascularization and other vascular surgical procedures and areduction in the required amount of either agent to achieve theanti-restenotic effect.

Trichostatin A may be affixed to any of the medical devices describedherein utilizing any of the techniques and materials described herein.For example, trichostatin A may be affixed to a stent, with or withoutpolymers, or delivered locally via a catheter-based delivery system. Thetrichostatin A may substantially block neointimal formation by localvascular application by virtue of a substantially complete and potentblockade of human coronary artery smooth muscle cell proliferation. Thecombination of rapamycin and trichostatin A, as well as other agentswithin its pharmacologic class, represents a new therapeutic combinationthat may be more efficacious against restenosis/neointimal thickeningthen rapamycin alone. In addition, different doses of the combinationmay lead to additional gains of inhibition of the neointimal growth thanthe simple additive effects of rapamycin plus trichostatin A. Thecombination of rapamycin and trichostatin A may be efficacious towardsother cardiovascular diseases such as vulnerable atherosclerotic plaque.

In yet another alternate exemplary embodiment, rapamycin may be utilizedin combination with mycophenolic acid. Like rapamycin, mycophenolic acidis an antibiotic, an anti-inflammatory and an immunosuppressive agent.Rapamycin, as previously stated, acts to reduce lymphocyte proliferationby arresting cells in the G1 phase of the cell cycle through theinhibition of the mammalian target of rapamycin. The downstream effectsof rapamycin on the mammalian target of rapamycin block subsequentactivity of cell cycle associated protein kinases. In contrast,mycophenolic acid inhibits immune cell proliferation in the S phase ofthe cell cycle through the inhibition of inosine monophosphatedehydrogenase, an enzyme necessary for purine biosynthesis. In additionto their immunosuppressive and anti-inflammatory effects, rapamycin andmycophenolic acid are each potent inhibitors of human coronary arterysmooth muscle cell proliferation.

As rapamycin and mycophenolic acid act through different molecularmechanisms affecting cell proliferation at different phases of the cellcycle, it is possible that these agents, when combined on a drug elutingstent or any other medical device as defined herein, my potentiate eachothers anti-restenotic activity by down regulating both smooth muscleand immune cell proliferation by different mechanisms.

Referring to FIG. 52, there is illustrated, in graphical format, theanti-proliferative activity of rapamycin, with varying concentrations ofmycophenolic acid in non-synchronized cultured human coronary arterysmooth muscle cells stimulated with two percent fetal bovine serum. Themultiple curves represent various concentrations of mycophenolic acidranging from zero to one thousand nanomolar concentrations. As seen inFIG. 52, the addition of mycophenolic acid to cells treated withrapamycin resulted in a leftward and upward shift of theanti-proliferative rapamycin dose response curve, indicating thatmycophenolic acid potentiates the anti-proliferative activity ofrapamycin in coronary artery smooth muscle cells. This potentiationobserved in cultured coronary artery smooth muscle cells preferablytranslates to an enhancement in anti-restenotic efficacy followingvascular injury and a reduction in the required amount of either agentto achieve the desired anti-restenotic effect.

FIG. 53 is a graphical representation of the in vivo release kinetics ofrapamycin from a combination of rapamycin, mycophenolic acid and apolymer in porcine pharmacokinetics studies. In the study, the rapamycinand mycophenolic acid are incorporated into an EVA/BMA polymer basecoat.The total weight of the basecoat is six hundred micro grams, with boththe rapamycin and mycophenolic acid comprising thirty percent, byweight, of the basecoat (one hundred eighty micro grams rapamycin, onehundred eighty micro grams mycophenolic acid and two hundred forty micrograms EVA/BMA). Curve 5302 represents the release of rapamycin from thebasecoat when no topcoat is utilized. Curve 5304 represents the releaseof rapamycin from the basecoat when a one hundred micro grams BMAtopcoat is utilized. Curve 5306 represents the release of rapamycin fromthe basecoat when a two hundred micro grams BMA topcoat is utilized. TheBMA topcoat does slow the release of rapamycin from the basecoat, whichin turn provides a mechanism for greater drug release control.

FIG. 54 is a graphical representation of the in vivo release kinetics ofmycophenolic acid from a combination of rapamycin, mycophenolic acid anda polymer in porcine pharmacokinetics studies. In the study, therapamycin and mycophenolic acid are incorporated into an EVA/BMA polymerbasecoat. The total weight of the basecoat is six hundred micro grams,with both the rapamycin and mycophenolic acid comprising thirty percent,by weight, of the basecoat (one hundred eighty micro grams rapamycin,one hundred eighty micro grams mycophenolic acid and two hundred fortymicro grams EVA/BMA). Curve 5402 represents the release of mycophenolicacid from the basecoat when no topcoat is utilized. Curve 5404represents the release of mycophenolic acid from the basecoat when a onehundred micro grams BMA topcoat is utilized. Curve 5406 represents therelease of mycophenolic acid from the basecoat when a two hundred microgram BMA topcoat is utilized. Similarly to the rapamycinpharmacokinetics, the BMA topcoat does slow the release of mycophenolicacid from the basecoat, which in turn provides a mechanism for greaterdrug release control. However, mycophenolic acid elutes more completelyover a shorter duration than the rapamycin.

FIG. 55 is a graphical representation of the in vitro release kineticsof rapamycin from a combination of rapamycin and mycophenolic acid. Inthe study, the rapamycin and mycophenolic acid are incorporated into anEVA/BMA polymer basecoat. The total weight of the basecoat is sixhundred micro grams, with both the rapamycin and mycophenolic acidcomprising thirty percent, by weight, of the basecoat (one hundredeighty micro grams rapamycin, one hundred eighty micro gramsmycophenolic acid and two hundred forty micro grams EVA/BMA). The invitro tests were run twice for each coating scenario. Curves 5502represent the release of rapamycin from the basecoat when no topcoat isutilized. Curves 5504 represent the release of rapamycin from thebasecoat when a one hundred micro grams BMA topcoat is utilized. Curves5506 represent the release of rapamycin from the basecoat when a twohundred micro grams BMA topcoat is utilized. The BMA topcoat does slowthe release of rapamycin from the basecoat in in vitro testing; however,the release rates are faster than in the in vivo testing.

FIG. 56 is a graphical representation of the in vivo release kinetics ofboth rapamycin and mycophenolic acid in porcine pharmacokineticsstudies. In this study, the rapamycin and mycophenolic acid areincorporated in a PVDF polymer basecoat with a PVDF topcoat. The totalweight of the basecoat is six hundred micro grams with the rapamycin andmycophenolic acid equally comprising two thirds, by weight, of thebasecoat. The topcoat is two hundred micro grams. Curve 5602 representsthe release rate of mycophenolic acid and curve 5604 represents therelease rate of rapamycin. As can be readily seen from the figure,rapamycin has a slower release rate than that of mycophenolic acid,which is consistent with the results found with an EVA/BMA basecoat andBMA topcoat. However, an EVA/BMA basecoat with a BMA topcoat appears toslow the release rate and thereby provide more control of the releaserate or elution rate than a PVDF basecoat and PVDF topcoat.

In yet another alternate exemplary embodiment, rapamycin may be utilizedin combination with cladribine. Cladribine (2-chlorodeoxyadenosine or2-CdA) is the 2-chloro-2′-deoxy derivative of the purine nucleoside,adenosine. Cladribine is resistant to degradation by adenosinedeaminase, one of two intracellular adenine nucleotide regulatoryenzymes, found in most cells. The other enzyme, 5′-nucleotidase, ispresent in variable amounts in different cell types (Carson et al.,1983). After initial phosphorylation to its monophosphate derivative bythe intracellular enzyme, deoxycytidine kinase, 2-CdA is converted to a5′-triphosphate (2-CdATP) which accumulates in levels which may be fiftyfold greater than normal dATP levels. Thus, in cells such as leukocytes,which contain a high ratio (>0.04) of deoxycytidine kinase to5′-nucleotidase, 2-CdA and its subsequent metabolites will tend toaccumulate in pharmacological concentrations (Carson et al., 1983). Suchhigh levels of a nucleoside triphosphate are known to inhibit the enzymeribonucleotide reductase in rapidly dividing cells, thus preventingsynthesis of deoxynucleotides required for DNA synthesis.

In resting cells, 2-CdATP is incorporated into DNA which results insingle strand breaks. Breaks in DNA results in the activation of poly(ADP-ribose) polymerase which in turn leads to a depletion of NAD, ATPand a disruption of cell metabolism (Carson et al., 1986; Seto et al.,1985). Further activation of a Ca²⁺/Mg²⁺-dependent endonuclease resultsin cleavage of the damaged DNA into fragments leading to programmed celldeath (apoptosis). Thus, 2-CdA may be cytotoxic to both resting anddividing cells (Beutler, 1992). Cladribine has shown activity in othercell types known to play a role in the inflammatory process whichaccompanies restenosis. Additionally, data presented herein demonstratethat cladribine also possesses an ability to inhibit smooth muscle cellproliferation, an action previously unknown for cladribine (seeCladribine Example). Therefore, cladribine may possess a unique spectrumof therapeutic action, including the prevention of the leukocyteaccumulation known to occur at sites of arterial injury and inflammationand the prevention of smooth muscle hyperplasia which results fromangioplasty and stent implantation.

Cladribine Example

To assess the ability of cladribine to prevent cell proliferation, humansmooth muscle or endothelial cells (Clonetics, Walkersville, Md.) wereseeded at a density of 2000 cells/cm² (approximately 3600 cells/well)into each well of 12-well plates and cultured with 1.5 ml of growthmedium containing five percent fetal calf serum (FCS). After twenty-fourhours, the growth medium was changed and fresh medium containing 10ng/ml platelet-derived growth factor AB (PDGF AB; LIFE Technologies), aswell as various concentrations of cladribine (0.001-10,000 nM) wereadded with triplicate wells. Medium was replaced with freshcladribine-containing medium after three days. On day six, cells weredetached by trypsinization to yield a cell suspension, lightlycentrifuged to pellet and then counted manually using a Neubauerhemocytometer system. Cell viability was assessed by trypan blueexclusion.

Table 7 provides the percent inhibition of the various testedconcentrations of cladribine on human smooth muscle and endothelialcells in culture. Cladribine produced a concentration-related decreasein the proliferation of both smooth muscle and endothelial cells in thismodel system. IC₅₀ values (concentration required to produce a reductionin proliferation to 50 percent of the vehicle-treated cell count) forthe inhibition of smooth muscle cell and endothelial cell growth were 23nanomolar and 40 nanomolar, respectively. Cladribine was thusapproximately twice as potent as an inhibitor of smooth muscle cells asit was as an inhibitor of endothelial cells. Both IC₅₀ values are withinthe range of inhibitory concentrations reported for cladribine on humanmonocytes (Carrera et al., J. Clin. Invest. 86:1480-1488, 1990) andnormal bone marrow, lymphocytic and lymphoblastic cell lines (Carson, D.A. et al., Blood 62: 737-743, 1983). Thus, concentrations of cladribineknown to be effective at inhibiting peripheral leukemic blood cellproliferation and bone marrow cells are also effective at inhibitingproliferating vascular smooth muscle and endothelial cells. Cladribinemay therefore be therapeutically useful for inhibition of the intimalsmooth muscle cell proliferation which accompanies stent implantation.

TABLE 7.0 Inhibition of human vascular cell proliferation withcladribine. Cladribine (nM) Control Vehicle 0.001 0.01 0.1 1 10 100 100010,000 SMC 100 108 — 104 86 85 54 58 12 −4 EC 100 100 100 90 79 75 59 5735 10 Values represent % of PDGF-stimulated increase in cell count. Each% is the mean of triplicate determinations. SMC, smooth muscle cells;EC, endothelial cells.

Cladribine or 2-chlorodeoxyadenosine is a purine antimetabolite prodrugthat undergoes intracellular phosphorylation and incorporation into theDNA of proliferating cells. This leads to DNA strand breaks andinhibition of DNA synthesis. Cladribine is capable of arresting cells atthe G1/S phase interface. Thus it is possible that cladribine mayinhibit vascular smooth muscle cell proliferation and inhibitinflammatory cell function secondary to revascularization procedures.

FIG. 58 illustrates, in graphical format, the anti-proliferativeactivity of cladribine in non-synchronized cultured human coronaryartery smooth muscle cells stimulated with two percent fetal bovineserum. As illustrated, cladribine completely inhibits human coronaryartery smooth muscle cell proliferation and has an anti-proliferativeIC50 of approximately 241 nanomolar. It is therefore possible thatcladribine itself, delivered locally, may substantially inhibitneointimal formation following vascular injury.

As rapamycin and cladribine act through different molecular mechanismsaffecting cell proliferation at different phases of the cell cycle, itis possible that these agents, when combined on a drug eluting stent orany other medical device as defined herein, may potentiate each other'santi-restenotic activity by downregulating both smooth muscle cell andimmune cell proliferation by different mechanisms. In non-synchronizedcultured human coronary artery smooth muscle cells studies, the additionof cladribine to cells treated with rapamycin resulted in a leftward andupward shift of the anti-proliferative rapamycin dose response curves,as set forth in detail below, suggesting that cladribine does in factpotentiate the anti-proliferative activity of rapamycin in coronaryartery smooth muscle cells. The combination of rapamycin and cladribinemay be utilized to enhance the anti-restenotic efficacy followingvascular injury and a reduction in the required amount of either agentto achieve the anti-restenotic effect. The combination may beparticularly relevant to the subpopulations of patients that areresistant to single drugs regimens such as rapamycin or paclitaxelcoated stents.

Referring to FIG. 57, there is illustrated, in graphical format, theanti-proliferative activity of rapamycin, with varying concentrations ofcladribine in non-synchronized cultured human coronary artery smoothmuscle cells stimulated with two percent fetal bovine serum. Themultiple curves represent various concentrations of cladribine rangingfrom zero to nine hundred nanomolar concentrations. As seen in FIG. 57,the addition of cladribine to cells treated with rapamycin increases thepercent inhibition of rapamycin alone. Curve 5702 represents theresponse of just rapamycin. Curve 5704 represents the response ofrapamycin in combination with a 56.25 nanomolar concentration ofcladribine. Curve 5706 represents the response of rapamycin incombination with a 112.5 nanomolar concentration of cladribine. Curve5708 represents the response of rapamycin in combination with a 225nanomolar concentration cladribine. Curve 5710 represents the responseof rapamycin in combination with a 450 nanomolar concentration ofcladribine. Curve 5712 represents the response of rapamycin incombination with a 900 nanomolar concentration of cladribine. Asillustrated, the percent inhibition increases substantially as the doseof cladribine increases.

FIG. 59 is a graphical representation of the in vitro release kineticsof cladribine from non-sterile cladribine coatings in a PVDF/HFPbasecoat incorporated in a twenty-five percent ethanol/water releasemedium at room temperature. The basecoat comprises a ratio of PVDF/HFP(85/15) and cladribine. Cladribine comprises thirty percent of thebasecoat. The topcoat also comprises an 85/15 ratio of PVDF and HFP, butno cladribine. Curve 5902 represents the release kinetics of cladribinewherein the basecoat weight is six hundred micrograms (one hundredeighty micrograms cladribine). Curve 5904 represents the releasekinetics of cladribine wherein the basecoat weight is one thousand eighthundred micrograms (five hundred forty micrograms cladribine). Curve5906 represents the release kinetics of cladribine wherein the basecoatweight is six hundred micrograms (one hunded eighty microgramscladribine) and the topcoat weight is one hundred micrograms. Curve 5908represents the release kinetics of cladribine wherein the basecoatweight is one thousand eight hundred micrograms (five hundred fortymicrograms cladribine) and the topcoat is three hundred micrograms.Curve 5910 represents the release kinetic of cladribine wherein thebasecoat weight is six hundred micrograms (one hundred eighty microgramscladribine) and the topcoat is three hundred micrograms. As can be seenfrom the various curves, an increase in topcoat weight or thickness ledto a decrease in the release rate of cladribine from the coating.

FIG. 60 is a graphical representation of the in vitro release kineticsof cladribine from a sterile PVDF/HFP coating incorporated in atwenty-five percent ethanol/water release medium at room temperature.Curve 6002 represents the release kinetics where no topcoat is utilizedand curve 6004 represents the release kinetics where a topcoat isutilized. As seen from the figure, a three-times topcoat led to adrastic decrease of release rate of cladribine.

FIG. 61 is a graphical representation of the in vivo release kinetics ofcladribine from a polymeric coating on Bx Velocity® stents, availablefrom Cordis Corporation, implanted in a Yorkshire pig. The basecoatcomprises an 85/15 ratio of PVDF and HFP and cladribine for a totalcombined weight of one thousand eight hundred micrograms (cladribinecomprising thirty percent of the total weight). The topcoat comprises an85/15 ratio of PVDF/HFP and no cladribine. The total weight of thetopcoat is three hundred micrograms. As can be seen from curve 6102,after the first day, the elution of cladribine levels off significantly.

FIG. 62 is a graphical representation of the in vivo release kinetics ofrapamycin from a combination of rapamycin, cladribine and a polymer inporcine pharmacokinetics studies. In the study, the rapamycin andcladribine are incorporated into an EVA/BMA (50/50) polymer basecoat.The basecoat is applied to Bx Velocity® stents and implanted intoYorkshire pigs. Curve 6202 represents the release kinetics of rapamycinfrom a six hundred microgram basecoat comprising one hundred eightymicrograms rapamycin, one hundred eighty micrograms cladribine and twohundred forty micrograms EVA/BMA with a two hundred microgram topcoat ofBMA. Curve 6204 represents the release kinetics of rapamycin from a sixhundred microgram basecoat comprising one hundred twenty microgramsrapamycin, one hundred twenty micrograms cladribine and three hundredsixty micrograms EVA/BMA with a two hundred microgram topcoat of BMA.Curve 6206 represents the release kinetics of rapamycin from a sixhundred microgram basecoat comprising one hundred eighty microgramsrapamycin, ninety micrograms cladribine and three hundred thirtymicrograms EVA/BMA with a two hundred microgram topcoat of BMA. Therelease rates of rapamycin from the polymeric coating are substantiallysimilar to one another.

FIG. 63 is a graphical representation of the in vivo release kinetics ofcladribine from a combination of rapamycin, cladribine and a polymer inporcine pharmacokinetics studies. In the study, the rapamycin andcladribine are incorporated into an EVA/BMA polymer basecoat. Thebasecoat is applied to Bx Velocity® stents and implanted into Yorkshirepigs. Curve 6302 represents the release kinetics of cladribine from asix hundred microgram basecoat comprising one hundred eighty microgramsrapamycin, one hundred eighty micrograms cladribine and two hundredforty micrograms EVA/BMA with a two hundred microgram topcoat of BMA.Curve 6304 represents the release kinetics of cladribine from a sixhundred microgram basecoat comprising one hundred twenty microgramsrapamycin, one hundred twenty micrograms cladribine and three hundredsixty micrograms EVA/BMA with a two hundred microgram topcoat of BMA.Curve 6306 represents the release kinetics of cladribine from a sixhundred microgram basecoat comprising one hundred eighty microgramsrapamycin, ninety micrograms cladribine and three hundred thirtymicrograms EVA/BMA with a two hundred microgram topcoat of BMA. Curve6308 represents the release kinetics of cladribine from a six hundredmicrogram basecoat comprising no rapamycin, one hundred eightymicrograms of cladribine and four hundred micrograms EVA/BMA with a twohundred microgram BMA topcoat. As illustrated in FIG. 63, there appearsto be some degree of controlled cladribine elution from the polymericstent coating; however, it may be generally concluded that cladribineelutes more rapidly than rapamycin as is seen from a comparison to theresults presented with respect to FIG. 62. In general, it appears thatthe thicker or heavier the topcoat, the slower the elution rate,regardless of the agent.

In yet another alternate exemplary embodiment, topotecan in combinationwith rapamycin may be utilized to prevent restenosis following vascularinjury. Rapamycin acts to reduce lymphocyte and smooth muscle cellproliferation by arresting cells in the G1 phase of the cell cyclethrough the inhibition of the mammalian target of rapamycin. Subsequentactivity of cell cycle associated protein kinases is blocked by thedownstream effects of rapamycin on the mammalian target of rapamycin.Topotecan is an analog of camptothecin that interfaces with DNAsynthesis through the inhibition of topoisomerase I. This inhibitionleads to an accumulation of DNA double strand breaks and an arrest ofcell division at the S phase of the cell cycle. Topotecan has been shownto inhibit human coronary artery smooth muscle cell proliferation (Brehmet al., 2000).

Camptothecin is a quinoline-based alkaloid found in the barks of theChinese camptotheca tree and the Asian nothapodytes tree. Camptothecin,aminocamptothecin, amerogentin, CPT-11 (irinotecan), DX-8951f andtopotecan are all DNA topoisomerase I inhibitors. Topotecan, irinotecanand camptothecin belong to the group of medicines or agents generallyreferred to as anti-neoplastics and are utilized to treat various formsof cancer, including cancer of the ovaries and certain types of lungcancer. Camptothecin may be particularly advantageous in local deliverybecause of its high lipid solubility and poor water solubility. Poorwater solubility may help retain the drug near the release site for alonger period of action time, potentially covering more cells as theycycle. High lipid solubility may lead to increased penetration of thedrug through the lipid cellular membrane, resulting in better efficacy.

As rapamycin and topotecan (and the analogs camptothecin and irinotecan)act through different molecular mechanisms affecting cell proliferationat different phases of the cell cycle, it is possible that these agents,when combined on a drug eluting stent or any other medical device asdefined herein, may potentiate each other's anti-restenotic activity bydownregulating both smooth muscle cell and immune cell proliferation(inflammatory cell proliferation) by distinct multiple mechanisms. Insynchronized cultured human coronary artery smooth muscle cells studies,the addition of topotecan to cells treated with rapamycin resulted in aleftward and upward shift of the anti-proliferative rapamycin doseresponse curves, as set forth in detail below, suggesting thattopotecan, and by extension, other agents in the topoisomerase Iinhibitor class, does in fact potentiate the anti-proliferative activityof rapamycin in coronary artery smooth muscle cells. The combination ofrapamycin and topotecan may be utilized to enhance the anti-restenoticefficacy following vascular injury and a reduction in the requiredamount of either agent to achieve the anti-restenotic effect. Thecombination may be particularly relevant to the subpopulations ofpatients that are resistant to single drug regimens such as rapamycin orpaclitaxel coated stents.

Referring to FIG. 64, there is illustrated, in graphical format, theanti-proliferative activity of rapamycin, with varying concentrations oftopotecan in synchronized cultured human coronary artery smooth musclecells stimulated with two percent fetal bovine serum. The multiplecurves represent various concentrations of topotecan ranging from zeroto three hundred nanomolar concentrations. Topotecan was found to benon-cytotoxic in a separate cell viability assay at concentrations up toone micromolar. As seen in FIG. 64, the addition of topotecan to cellstreated with rapamycin increases the percent inhibition of rapamycinalone. Curve 6402 represents the response of just rapamycin. Curve 6404represents the response of rapamycin in combination with a 18.8nanomolar concentration of topotecan. Curve 6406 represents the responseof rapamycin in combination with a 37.5 nanomolar concentration oftopotecan. Curve 6408 represents the response of rapamycin incombination with a 75 nanomolar concentration of topotecan. Curve 6410represents the response of rapamycin in combination with a 150 nanomolarconcentration of topotecan. Curve 6412 represents the response ofrapamycin in combination with a 300 nanomolar concentration oftopotecan.

The combination of rapamycin and topotecan, as well as othertopoisomerase I inhibitors, may provide a new therapeutic combinationthat may be more efficacious against restenosis/neointimal thickeningthan rapamycin alone. Different doses of rapamycin and topotecan, aswell as other topoisomerase I inhibitors, may lead to additional gainsof inhibition of the neointimal growth than the simple additive effectsof rapamycin and topotecan. In addition, the combination of topotecan,as well as other topoisomerase I inhibitors, may be efficacious in thetreatment of other cardiovascular diseases such as vulnerableatherosclerotic plaque.

The combination of rapamycin and topotecan, as well as othertopoisomerase I inhibitors, may be delivered to the target tissuethrough any number of means including stents and catheters. The deliveryof the drug combination may be achieved at different dose rates toachieve the desired effect, and as explained in more detailsubsequently, each drug may be loaded into different levels of thepolymeric matrix.

In yet another alternate exemplary embodiment, etoposide in combinationwith rapamycin may be utilized to prevent restenosis following vascularinjury. Rapamycin acts to reduce smooth muscle cell proliferation andlymphocyte proliferation by arresting cells in the G1 phase of the cellcycle through inhibition of the mammalian target of rapamycin.Subsequent activity of cell cycle associated protein kinases is blockedby the downstream effects of rapamycin on the mammalian target ofrapamycin. Etoposide is a cytostatic glucoside derivative ofpodophyllotoxin that interferes with DNA synthesis through inhibition oftopoisomerase II. This inhibition leads to DNA strand breaks and anaccumulation of cells in the G2/M phase of the cell cycle, G2/Mcheckpoint dysregulation and subsequent apoptosis.

Podophyllotoxin (podofilox) and its derivatives, etoposide andteniposide, are all cytostatic (antimitotic) glucosides. Podofilox is anextract of the mayapple. Proliferating cells are particularly vulnerableto podofilox. Etoposide is utilized to treat cancer of the testicles,lungs and other kinds of cancer. Etoposide and teniposide both block thecell cycle in two specific places. Etoposide and teniposide block thephase between the last division and the start of DNA replication andalso block the replication of DNA.

As rapamycin and etoposide act through different molecular mechanismsaffecting cell proliferation at different phases of the cell cycle, itis likely that these agents, when combined on a drug eluting stent orany other medical device as defined herein may potentiate each other'santi-restenotic activity by downregulating both smooth muscle cell andimmune cell proliferation (inflammatory cell proliferation) by distinctmultiple mechanisms. In non-synchronized cultured human coronary arterysmooth muscle cell studies, the addition of etoposide to cells treatedwith rapamycin resulted in a leftward and upward shift of theanti-proliferative rapamycin dose response curves, as set forth indetail below, suggesting that etoposide, and by extension, other agentsin the topoisomerase II inhibitor class, potentiate theanti-proliferative activity of rapamycin in coronary artery smoothmuscle cells. The combination of rapamycin and etoposide may be utilizedto enhance the anti-restenotic efficacy following vascular injury and areduction in the required amount of either agent to achieve theanti-restenotic effect. The combination may be particularly relevant tothe subpopulation of patients that are resistant to single drug regimenssuch as rapamycin or paclitaxel coated stents.

Referring to FIG. 65, there is illustrated, in graphical format, theanti-proliferative activity of rapamycin with varying concentrations ofetoposide in synchronized cultured human coronary artery smooth musclecells stimulated with two percent fetal bovine serum. The multiplecurves represent various concentrations of etoposide ranging from zeroto eight hundred nanomolar concentrations. Etoposide was found to benon-cytotoxic in a cell viability assay at concentrations up to tenmicromolar. As seen in FIG. 65, the addition of etoposide to cellstreated with rapamycin increases the percent inhibition of rapamycinalone. Curve 6502 represents the response of just rapamycin. Curve 6504represents the response of rapamycin in combination with a 255.7nanomolar concentration of etoposide. Curve 6506 represents the responseof rapamycin in combination with a 340.04 nanomolar concentration ofetoposide. Curve 6508 represents the response of rapamycin incombination with a 452.3 nanomolar concentration of etoposide. Curve6510 represents the response of rapamycin in combination with a 601.5nanomolar concentration of etoposide. Curve 6512 represents the responseof rapamycin in combination with an eight-hundred nanomolarconcentration of etoposide.

The combination of rapamycin and etoposide, as well as other cytostaticglucosides, including podophyllotoxin, its derivatives and teniposide,may provide a new therapeutic combination that may be more efficaciousagainst restenosis/neointimal thickening than rapamycin alone. Differentdoses of rapamycin and etoposide, as well as other cytostaticglucosides, including podophyllotoxin, its derivatives and teniposide,may lead to additional gains of inhibition of the neointimal growth thanthe simple additive effects of rapamycin and etoposide. In addition, thecombination of etoposide, as well as other cytostatic glucosides,including podophyllotoxin, its derivatives and teniposide, may beefficacious in the treatment of other cardiovascular diseases such asvulnerable atherosclerotic plaque.

The combination of rapamycin and etoposide, as well as other cytostaticglucosides, including podophyllotoxin, its derivatives and teniposide,may be delivered to the target tissue through any number of meansincluding stents and catheters. The delivery of the drug combination maybe achieved at different dose rates to achieve the desired effect, andas explained in more detail subsequently, each drug may be loaded intodifferent levels of the polymeric matrix.

In yet another alternate exemplary embodiment, Panzem® may be utilizedalone or in combination with rapamycin to prevent restenosis followingvascular injury. Rapamycin or sirolimus acts to reduce lymphocyte andsmooth muscle cell proliferation by arresting cells in the G1 phase ofthe cell cycle through the inhibition of the mammalian target ofrapamycin (mTOR). Rapamycin or sirolimus has shown excellentanti-restenotic effects when administered during revascularizationprocedures using drug eluting stents. In recent clinical trials, theCypher® stent, available from Cordis Corporation, which containsrapamycin or sirolimus in a polymer coating, consistently demonstratedsuperior efficacy against restenosis after the implantation of the stentas compared to a bare metal stent. Although the local delivery ofrapamycin from a drug eluting stent or other medical device is effectivein reducing restenosis, further reductions in neointimal hyperplasiawould benefit certain patient populations. Thus, the combination ofrapamycin with another agent, for example, another anti-proliferativeagent from a stent or other medical device may further reducefibroproliferative vascular responses secondary to procedures involvingvascular injury.

Panzem®, or 2-methoxyestradiol (2ME2) is a naturally occurringmetabolite of endogenous estrogen. Its many properties provide for awide range of potential formulations for drug delivery to treat numerousindications. Panzem® has been shown to exhibit anti-cancer activity inpatients with breast cancer, prostate cancer and multiple myeloma.Panzem® is a by-product of the metabolism estrogen and is normallypresent in the body in small amounts. Panzem®; however, does not actlike a hormone. Panzem® is a potent inhibitor of angiogenesis, which iswhat makes it such an effective anti-tumor agent. Essentially, Panzem®inhibits the formation of new blood vessels that supply oxygen andnutrients to tumor cells. Panzem® also appears to have multiple directand indirect anti-myeloma effects as briefly described above.

Panzem®, 2-methoxyestradiol (2ME2) or methoxy-β-estradiol is, asdescribed above, a product of estrogen metabolism and is currently beingevaluated clinically for a variety of oncologic indications. Panzem® hasanti-angiogenic activity, blocks the production of vascular endothelialgrowth factor and directly inhibits the growth of a number of tumor celltypes. Panzem® is also proapoptotic (programmed cell death) to myelomacells. Panzem® has been found to upregulate the DR-5 receptor (of theTNF receptor family) number responsible for TRAIL-mediated apoptosis(AACR, 2003) and has microtubule stabilizing properties and reduceshypoxia-inducible factor-1 (AACR, 2003). In addition, as illustrated indetail below, Panzem® reduces human coronary artery smooth muscle cellproliferation without negatively impacting coronary artery smooth musclecell viability.

Referring to FIG. 66, there is illustrated, in graphical format, theanti-proliferative activity of Panzem® in synchronized cultured humancoronary artery smooth muscle cells stimulated with two percent fetalbovine serum. As illustrated by curve 6600, Panzem® is an extremelyeffective inhibitor of human coronary artery smooth muscle cellproliferation in vitro. FIG. 67 illustrates, in graphical format, theanti-proliferative activity of rapamycin or sirolimus in synchronizedcultured human coronary artery smooth muscle cells stimulated with twopercent fetal bovine serum. As can be seen between a comparison betweencurves 6700 and 6600, both agents are effective in the in vitro studies.

As rapamycin or sirolimus and Panzem® or other estrogen receptormodulators act to inhibit cell proliferation through different molecularmechanisms, it is possible that these agents, when combined on a drugeluting stent or other medical device as defined herein, may potentiateeach other's anti-restenotic activity by downregulating both smoothmuscle and immune cell proliferation (inflammatory cell proliferation)by distinct multiple mechanisms. FIG. 68 illustrates the potentiation ofrapamycin by Panzem® on the anti-proliferative effects of rapamycin incoronary artery smooth muscle cells. This potentiation of rapamycinanti-proliferative activity by Panzem® and related compounds maytranslate into an enhancement in anti-restenotic efficacy followingvascular injury during revascularization and other vascular surgicalprocedures and a reduction in the required amount of either agent toachieve the anti-restenotic effect. In addition, the local applicationof Panzem® and related compounds, alone or in combination with rapamycinmay be therapeutically useful in treating vulnerable plaque.

Referring to FIG. 68, there is illustrated, in graphical format, theanti-proliferative activity of rapamycin with varying concentrations ofPanzem® in synchronized cultured human coronary artery smooth musclecells stimulated with two percent fetal bovine serum. The multiplecurves represent various concentrations of Panzem® ranging from zero to100 micromolar concentrations. As seen in FIG. 68, the addition ofPanzem® to cells treated with rapamycin increases the percent ofinhibition of rapamycin alone. Curve 6802 represents the response ofjust rapamycin. Curve 6804 represents the response of rapamycin incombination with a 0.813 micromolar concentration of Panzem®. Curve 6806represents the response of rapamycin in combination with a 2.71micromolar concentration of Panzem®. Curve 6808 represents the responseof rapamycin in combination with a 9.018 micromolar concentration ofPanzem®. Curve 6810 represents the response of rapamycin in combinationwith a 30.03 micromolar concentration of Panzem®. Curve 6812 representsthe response of rapamycin in combination with a 100 micromolarconcentration of Panzem®.

In vitro cytotoxicity tests or assays may be utilized to determine ifdrugs, agents and/or compounds are potentially toxic and the level oftoxicity. Essentially, in vitro cytotoxicity assays determine acutenecrotic effects by a drug causing direct cellular damage. The ideabehind these assays is that toxic chemicals affect basic functions ofcells which are common to all cells. Typically, a control is utilized todetermine baseline toxicity. There are a number of different assays thatmay be utilized. In the present invention, the cytotoxicity assayutilized is based upon the measurement of cellular metabolic activity. Areduction in metabolic activity is an indication of cellular damage.Tests that can measure metabolic function measure cellular ATP levels ormitochondrial activity via MTS metabolism. FIG. 69 is a graphicalrepresentation of the results of an MTS assay of Panzem®. Asillustrated, concentrations of Panzem® ranging from 6.6 nanomolar to30,000.00 nanomolar concentrations were tested without any significantfluctuations in cytotoxicity. The results of the assay indicate thatPanzem® concentrations up to 30,000.00 nanomolar do not reduce humancoronary artery smooth muscle cell survival.

FIG. 70 is a graphical representation of the in vitro release kineticsof rapamycin or sirolimus from a combination of rapamycin and Panzem®.In the study, the rapamycin and Panzem® are incorporated into differentlayers of a polymeric coating. In this study, a Bx Velocity stent iscoated with a four hundred microgram inner layer and a three hundredmicrogram outer layer. The inner layer comprises forty-five percentPanzem® and fifty-five percent EVA/BMA (50/50). The outer layercomprises forty percent rapamycin and sixty percent EVA/BMA (50/50).There is no topcoat of just polymer in this study. Curve 7000illustrates the release kinetics of rapamycin from the combination.

FIG. 71 is a graphical representation of the in vitro release kineticsof Panzem® from a combination of rapamycin or sirolimus and Panzem®. Inthe study, the rapamycin and Panzem® are incorporated into differentlayers of a polymeric coating. In this study, a Bx Velocity stent iscoated with a four hundred microgram inner layer and a three hundredmicrogram outer layer. The inner layer comprises forty-five percentPanzem® and fifty-five percent EVA/BMA (50/50). The outer layercomprises forty percent rapamycin and sixty percent EVA/BMA (50/50).There is no topcoat of just polymer in this study. Curve 7100illustrates the release kinetics of Panzem® from the coating. As may beseen from a comparison of FIGS. 70 and 71, rapamycin elutes more slowlythan Panzem® under the conditions of the test.

As is explained in more detail subsequently, a combination ofincompatible polymers may be utilized in combination with rapamycin andmycophenolic acid, rapamycin and trichostatin A, rapamycin andcladribine, rapamycin and topotecan, rapamycin and etoposide, rapamycinand Panzem and/or any of the drugs, agents and/or compounds describedherein to provide for the controlled local delivery of these drugs,agents and/or compounds or combinations thereof from a medical device.In addition, these incompatible polymers may be utilized in variouscombinations to control the release rates of individual agents fromcombinations of agents. For example, from the tests described above, itis seen that mycophenolic acids elute more quickly than rapamycin.Accordingly, the correct combination of incompatible polymers may beutilized to ensure that both agents elute at the same rate if sodesired.

The coatings and drugs, agents or compounds described above may beutilized in combination with any number of medical devices, and inparticular, with implantable medical devices such as stents andstent-grafts. Other devices such as vena cava filters and anastomosisdevices may be used with coatings having drugs, agents or compoundstherein. The exemplary stent illustrated in FIGS. 1 and 2 is a balloonexpandable stent. Balloon expandable stents may be utilized in anynumber of vessels or conduits, and are particularly well suited for usein coronary arteries. Self-expanding stents, on the other hand, areparticularly well suited for use in vessels where crush recovery is acritical factor, for example, in the carotid artery. Accordingly, it isimportant to note that any of the drugs, agents or compounds, as well asthe coatings described above, may be utilized in combination withself-expanding stents which are known in the art.

Surgical anastomosis is the surgical joining of structures, specificallythe joining of tubular organs to create an intercommunication betweenthem. Vascular surgery often involves creating an anastomosis betweenblood vessels or between a blood vessel and a vascular graft to createor restore a blood flow path to essential tissues. Coronary arterybypass graft surgery (CABG) is a surgical procedure to restore bloodflow to ischemic heart muscle whose blood supply has been compromised byocclusion or stenosis of one or more of the coronary arteries. Onemethod for performing CABG surgery involves harvesting a saphenous veinor other venous or arterial conduit from elsewhere in the body, or usingan artificial conduit, such as one made of Dacron® or GoreTex® tubing,and connecting this conduit as a bypass graft from a viable artery, suchas the aorta, to the coronary artery downstream of the blockage ornarrowing. It is preferable to utilize natural grafts rather thansynthetic grafts. A graft with both the proximal and distal ends of thegraft detached is known as a “free graft.” A second method involvesrerouting a less essential artery, such as the internal mammary artery,from its native location so that it may be connected to the coronaryartery downstream of the blockage. The proximal end of the graft vesselremains attached in its native position. This type of graft is known asa “pedicled graft.” In the first case, the bypass graft must be attachedto the native arteries by an end-to-side anastomosis at both theproximal and distal ends of the graft. In the second technique at leastone end-to-side anastomosis must be made at the distal end of the arteryused for the bypass. In the description of the exemplary embodimentgiven below reference will be made to the anastomoses on a free graft asthe proximal anastomosis and the distal anastomosis. A proximalanastomosis is an anastomosis on the end of the graft vessel connectedto a source of blood, for example, the aorta and a distal anastomosis isan anastomosis on the end of the graft vessel connected to thedestination of the blood flowing through it, for example, a coronaryartery. The anastomoses will also sometimes be called the firstanastomosis or second anastomosis, which refers to the order in whichthe anastomoses are performed regardless of whether the anastomosis ison the proximal or distal end of the graft.

At present, essentially all vascular anastomoses are performed byconventional hand suturing. Suturing the anastomoses is a time-consumingand difficult task, requiring much skill and practice on the part of thesurgeon. It is important that each anastomosis provide a smooth, openflow path for the blood and that the attachment be completely free ofleaks. A completely leak-free seal is not always achieved on the veryfirst try. Consequently, there is a frequent need for resuturing of theanastomosis to close any leaks that are detected.

The time consuming nature of hand sutured anastomoses is of specialconcern in CABG surgery for several reasons. Firstly, the patient isrequired to be supported on cardiopulmonary bypass (CPB) for most of thesurgical procedure, the heart must be isolated from the systemiccirculation (i.e. “cross-clamped”), and the heart must usually bestopped, typically by infusion of cold cardioplegia solution, so thatthe anastomosis site on the heart is still and blood-free during thesuturing of the anastomosis. Cardiopulminary bypass, circulatoryisolation and cardiac arrest are inherently very traumatic, and it hasbeen found that the frequency of certain post-surgical complicationsvaries directly with the duration for which the heart is undercardioplegic arrest (frequently referred to as the “crossclamp time”).Secondly, because of the high cost of cardiac operating room time, anyprolongation of the surgical procedure can significantly increase thecost of the bypass operation to the hospital and to the patient. Thus,it is desirable to reduce the duration of the crossclamp time and of theentire surgery by expediting the anastomosis procedure without reducingthe quality or effectiveness of the anastomoses.

The already high degree of manual skill required for conventionalmanually sutured anastomoses is even more elevated for closed-chest orport-access thoracoscopic bypass surgery, a newly developed surgicalprocedure designed to reduce the morbidity of CABG surgery as comparedto the standard open-chest CABG procedure. In the closed-chestprocedure, surgical access to the heart is made through narrow accessports made in the intercostal spaces of the patient's chest, and theprocedure is performed under thoracoscopic observation. Because thepatient's chest is not opened, the suturing of the anastomoses must beperformed at some distance, using elongated instruments positionedthrough the access ports for approximating the tissues and for holdingand manipulating the needles and sutures used to make the anastomoses.This requires even greater manual skill than the already difficultprocedure of suturing anastomoses during open-chest CABG surgery.

In order to reduce the difficulty of creating the vascular anastomosesduring either open or closed-chest CABG surgery, it would be desirableto provide a rapid means for making a reliable end-to-side anastomosisbetween a bypass graft or artery and the aorta or the native vessels ofthe heart. A first approach to expediting and improving anastomosisprocedures has been through stapling technology. Stapling technology hasbeen successfully employed in many different areas of surgery for makingtissue attachments faster and more reliably. The greatest progress instapling technology has been in the area of gastrointestinal surgery.Various surgical stapling instruments have been developed forend-to-end, side-to-side, and end-to-side anastomoses of hollow ortubular organs, such as the bowel. These instruments, unfortunately, arenot easily adaptable for use in creating vascular anastomoses. This ispartially due to the difficulty in miniaturizing the instruments to makethem suitable for smaller organs such as blood vessels. Possibly evenmore important is the necessity of providing a smooth, open flow pathfor the blood. Known gastrointestinal stapling instruments forend-to-side or end-to-end anastomosis of tubular organs are designed tocreate an inverted anastomosis, that is, one where the tissue foldsinward into the lumen of the organ that is being attached. This isacceptable in gastrointestinal surgery, where it is most important toapproximate the outer layers of the intestinal tract (the serosa). Thisis the tissue which grows together to form a strong, permanentconnection. However, in vascular surgery this geometry is unacceptablefor several reasons. Firstly, the inverted vessel walls would cause adisruption in the blood flow. This could cause decreased flow andischemia downstream of the disruption, or, worse yet, the flowdisruption or eddies created could become a locus for thrombosis whichcould shed emboli or occlude the vessel at the anastomosis site.Secondly, unlike the intestinal tract, the outer surfaces of the bloodvessels (the adventitia) will not grow together when approximated. Thesutures, staples, or other joining device may therefore be neededpermanently to maintain the structural integrity of the vascularanastomosis. Thirdly, to establish a permanent, nonthrombogenic vessel,the innermost layer (the endothelium) should grow together for acontinuous, uninterrupted lining of the entire vessel. Thus, it would bepreferable to have a stapling instrument that would create vascularanastomoses that are everted, that is folded outward, or which createdirect edge-to-edge coaptation without inversion.

At least one stapling instrument has been applied to performing vascularanastomoses during CABG surgery. This device, first adapted for use inCABG surgery by Dr. Vasilii I. Kolesov and later refined by Dr. EvgeniiV. Kolesov (U.S. Pat. No. 4,350,160), was used to create an end-to-endanastomosis between the internal mammary artery (IMA) or a vein graftand one of the coronary arteries, primarily the left anterior descendingcoronary artery (LAD). Because the device could only perform end-to-endanastomoses, the coronary artery first had to be severed and dissectedfrom the surrounding myocardium, and the exposed end everted forattachment. This technique limited the indications of the device tocases where the coronary artery was totally occluded, and thereforethere was no loss of blood flow by completely severing the coronaryartery downstream of the blockage to make the anastomosis. Consequently,this device is not applicable where the coronary artery is onlypartially occluded and is not at all applicable to making the proximalside-to-end anastomosis between a bypass graft and the aorta.

One attempt to provide a vascular stapling device for end-to-sidevascular anastomoses is described in U.S. Pat. No. 5,234,447, issued toKaster et al. for a Side-to-end Vascular Anastomotic Staple Apparatus.Kaster et al. provide a ring-shaped staple with staple legs extendingfrom the proximal and distal ends of the ring to join two blood vesselstogether in an end-to-side anastomosis. However, Kaster et al. does notprovide a complete system for quickly and automatically performing ananastomosis. The method of applying the anastomosis staple disclosed byKaster et al. involves a great deal of manual manipulation of thestaple, using hand operated tools to individually deform the distaltines of the staple after the graft has been attached and before it isinserted into the opening made in the aortic wall. One of the moredifficult maneuvers in applying the Kaster et al. staple involvescarefully everting the graft vessel over the sharpened ends of thestaple legs, then piercing the evened edge of the vessel with the staplelegs. Experimental attempts to apply this technique have proven to bevery problematic because of difficulty in manipulating the graft vesseland the potential for damage to the graft vessel wall. For speed,reliability and convenience, it is preferable to avoid the need forcomplex maneuvers while performing the anastomosis. Further bendingoperations must then be performed on the staple legs. Once the distaltines of the staple have been deformed, it may be difficult to insertthe staple through the aortotomy opening. Another disadvantage of theKaster et al. device is that the distal tines of the staple pierce thewall of the graft vessel at the point where it is evened over thestaple. Piercing the wall of the graft vessel potentially invitesleaking of the anastomosis and may compromise the structural integrityof the graft vessel wall, serving as a locus for a dissection or even atear, which could lead to catastrophic failure. Because the Kaster et alstaple legs only apply pressure to the anastomosis at selected points,there is a potential for leaks between the staple legs. The distal tinesof the staple are also exposed to the blood flow path at the anastomoticsite where it is most critical to avoid the potential for thrombosis.There is also the potential that exposure of the medial layers of thegraft vessel where the staple pierces the wall could be a site for theonset of intimal hyperplasia, which would compromise the long-termpatency of the graft as described above. Because of these potentialdrawbacks, it is desirable to make the attachment to the graft vessel asatraumatic to the vessel wall as possible and to eliminate as much aspossible the exposure of any foreign materials or any vessel layersother than a smooth uninterrupted intimal layer within the anastomosissite or within the graft vessel lumen.

A second approach to expediting and improving anastomosis procedures isthrough the use of anastomotic fittings for joining blood vesselstogether. One attempt to provide a vascular anastomotic fitting devicefor end-to-side vascular anastomoses is described in U.S. Pat. No.4,366,819, issued to Kaster for an Anastomotic Fitting. This device is afour-part anastomotic fitting having a tubular member over which thegraft vessel is evened, a ring flange which engages the aortic wall fromwithin the aortic lumen, and a fixation ring and a locking ring whichengage the exterior of the aortic wall. Another similar AnastomoticFitting is described in U.S. Pat. No. 4,368,736, also issued to Kaster.This device is a tubular fitting with a flanged distal end that fastensto the aortic wall with an attachment ring, and a proximal end with agraft fixation collar for attaching to the graft vessel. These deviceshave a number of drawbacks. Firstly, the anastomotic fittings describedexpose the foreign material of the anastomotic device to the blood flowpath within the arteries. This is undesirable because foreign materialswithin the blood flow path can have a tendency to cause hemolysis,platelet deposition and thrombosis. Immune responses to foreignmaterial, such as rejection of the foreign material or auto-immuneresponses triggered by the presence of foreign material, tend to bestronger when the material is exposed to the bloodstream. As such, it ispreferable that as much as possible of the interior surfaces of ananastomotic fitting that will be exposed to the blood flow path becovered with vascular tissue, either from the target vessel or from thegraft vessel, so that a smooth, continuous, hemocompatible endotheliallayer will be presented to the bloodstream. The anastomotic fittingdescribed by Kaster in the '819 patent also has the potential drawbackthat the spikes that hold the graft vessel onto the anastomotic fittingare very close to the blood flow path, potentially causing trauma to theblood vessel that could lead to leaks in the anastomosis or compromiseof the mechanical integrity of the vessels. Consequently, it isdesirable to provide an anastomosis fitting that is as atraumatic to thegraft vessel as possible. Any sharp features such as attachment spikesshould be placed as far away from the blood flow path and theanastomosis site as possible so that there is no compromise of theanastomosis seal or the structural integrity of the vessels.

Another device, the 3M-Unilink device for end-to-end anastomosis (U.S.Pat. Nos. 4,624,257; 4,917,090; 4,917,091) is designed for use inmicrosurgery, such as for reattaching vessels severed in accidents. Thisdevice provides an anastomosis clamp that has two eversion rings whichare locked together by a series of impaling spikes on their opposingfaces. However, this device is awkward for use in end-to-sideanastomosis and tends to deform the target vessel; therefore it is notcurrently used in CABG surgery. Due to the delicate process needed toinsert the vessels into the device, it would also be unsuitable forport-access surgery.

In order to solve these and other problems, it is desirable to providean anastomosis device which performs an end-to-side anastomosis betweenblood vessels or other hollow organs and vessels. It is also desirableto provide an anastomosis device which minimizes the trauma to the bloodvessels while performing the anastomosis, which minimizes the amount offoreign materials exposed to the blood flow path within the bloodvessels and which avoids leakage problems, and which promotes rapidendothelialization and healing. It is also desirable that the inventionprovide a complete system for quickly and automatically performing ananastomosis with a minimal amount of manual manipulation.

Anastomosis devices may be utilized to join biological tissues, and moreparticularly, joining tubular organs to create a fluid channel. Theconnections between the tubular organs or vessels may be made side toside, end to end and/or end to side. Typically, there is a graft vesseland a target vessel. The target vessel may be an artery, vein or anyother conduit or fluid carrying vessel, for example, coronary arteries.The graft vessel may comprise a synthetic material, an autologus vessel,a homologus vessel or a xenograft. Anastomosis devices may comprise anysuitable biocompatible materials, for example, metals, polymers andelastomers. In addition, there are a wide variety of designs andconfigurations for anastomosis devices depending on the type ofconnection to be made. Similarly to stents, anastomosis devices causesome injury to the target vessel, thereby provoking a response from thebody. Therefore, as in the case with stents, there is the potential forsmooth muscle cell proliferation which can lead to blocked connections.Accordingly, there is a need to minimize or substantially eliminatesmooth muscle cell proliferation and inflammation at the anastomoticsite. Rapamycin and/or other drugs, agents or compounds may be utilizedin a manner analogous to stents as described above. In other words, atleast a portion of the anastomosis device may be coated with rapamycinor other drug, agent and/or compound.

FIGS. 10-13 illustrate an exemplary anastomosis device 200 for an end toside anastomosis. The exemplary anastomosis device 200 comprises afastening flange 202 and attached staple members 204. As stated above,the anastomosis device may comprise any suitable biocompatible material.Preferably, the anastomosis device 200 comprises a deformablebiocompatible metal, such as a stainless steel alloy, a titanium alloyor a cobalt alloy. Also as stated above, a surface coating or surfacecoating comprising a drug, agent or compound may be utilized to improvethe biocompatibility or other material characteristics of the device aswell as to reduce or substantially eliminate the body's response to itsplacement therein.

In the exemplary embodiment, the fastening flange 202 resides on theinterior surface 206 of the target vessel wall 208 when the anastomosisis completed. In order to substantially reduce the risk of hemolysis,thrombogenesis or foreign body reactions, the total mass of thefastening flange 202 is preferably as small as possible to reduce theamount of foreign material within the target vessel lumen 210.

The fastening flange 202 is in the form of a wire ring with an internaldiameter, which when fully expanded, is slightly greater than theoutside diameter of the graft vessel wall 214 and of the opening 216made in the target vessel wall 208. Initially, the wire ring of thefastening flange 202 has a rippled wave-like shape to reduce thediameter of the ring so that it will easily fit through the opening 216in the target vessel wall 208. The plurality of staple members 204extend substantially perpendicular from the wire ring in the proximaldirection. In the illustrative exemplary embodiment, there are ninestaple members 204 attached to the wire ring fastening flange 202. Othervariations of the anastomosis device 200 might typically have from fourto twelve staple members 204 depending on the size of the vessels to bejoined and the security of attachment required in the particularapplication. The staple members 204 may be integrally formed with thewire ring fastening flange 202 or the staple members 204 may be attachedto the fastening flange 202 by welding, brazing or any other suitablejoining method. The proximal ends 218 of the staple members 204 aresharpened to easily pierce the target vessel wall 208 and the graftvessel wall 214. Preferably, the proximal ends 218 of the staple members204 have barbs 220 to improve the security of the attachment when theanastomosis device 200 is deployed. The anastomosis device 200 isprepared for use by mounting the device onto the distal end of anapplication instrument 222. The fastening flange 202 is mounted on ananvil 224 attached to the distal end of the elongated shaft 226 of theapplication instrument 222. The staple members 204 are compressed inwardagainst a conical holder 228 attached to the instrument 222 proximal tothe anvil 224. The staple members 204 are secured in this position by acap 230 which is slidably mounted on the elongated shaft 226. The cap230 moves distally to cover the sharpened, barbed proximal ends 218 ofthe staple members 204 and to hold them against the conical holder 228.The application instrument 222 is then inserted through the lumen 232 ofthe graft vessel 214. This may be done by inserting the applicationinstrument 222 through the graft vessel lumen 232 from the proximal tothe distal end of the graft vessel 214, or it may be done by backloading the elongated shaft 226 of the application instrument 222 intothe graft vessel lumen 232 from the distal end to the proximal end,whichever is most convenient in the case. The anvil 224 and conicalholder 228 on the distal end of the application instrument 222 with theanastomosis device 200 attached is extended through the opening 216 intothe lumen 210 of the target vessel.

Next, the distal end 234 of the graft vessel wall 214 is everted againstthe exterior surface 236 of the target vessel wall 208 with the graftvessel lumen 232 centered over the opening 216 in the target vessel wall208. The cap 230 is withdrawn from the proximal ends 218 of the staplemembers 204, allowing the staple members 204 to spring outward to theirexpanded position. The application instrument 222 is then drawn in theproximal direction so that the staple members pierce the target vesselwall 208 surrounding the opening 216 and the everted distil end 234 ofthe graft vessel 214.

The application instrument 222 has an annular staple former 238 whichsurrounds the outside of the graft vessel 214. Slight pressure on theeverted graft vessel wall from the annular staple former 238 during thepiercing step assists in piercing the staple members 204 through thegraft vessel wall 214. Care should be taken not to apply too muchpressure with the annular staple former 238 at this point in the processbecause the staple members 204 could be prematurely deformed before theyhave fully traversed the vessel walls. If desired, an annular surfacemade of a softer material, such as an elastomer, can be provided on theapplication instrument 222 to back up the vessel walls as the staplemembers 204 pierce through them.

Once the staple members 204 have fully traversed the target vessel wall208 and the graft vessel wall 214, the staple former 238 is brought downwith greater force while supporting the fastening flange 202 with theanvil 224. The staple members 204 are deformed outward so that thesharpened, barbed ends 218 pierce back through the everted distil end234 and into the target vessel wall 208 to form a permanent attachment.To complete the anastomosis, the anvil 224 is withdrawn through thegraft vessel lumen 232. As the anvil 224 passes through the wire ringfastening flange 202, it straightens out the wave-like ripples so thatthe wire ring flange 202 assumes its full expanded diameter.Alternately, the wire ring fastening flange 202 may be made of aresilient material so that the flange 202 may be compressed and held ina rippled or folded position until it is released within the targetvessel lumen 210, whereupon it will resume its full expanded diameter.Another alternate construction would be to move the anastomosis deviceof a shape-memory alloy so that the fastening flange may be compressedand inserted through the opening in the target vessel, whereupon itwould be returned to its full expanded diameter by heating the device200 to a temperature above the shape-memory transition temperature.

In the above-described exemplary embodiment, the staple members 204and/or the wire ring fastening flange 202 may be coated with any of theabove-described agents, drugs or compounds such as rapamycin to preventor substantially reduce smooth muscle wall proliferation.

FIG. 14 illustrates an alternate exemplary embodiment of an anastomosisdevice. FIG. 14 is a side view of an apparatus for joining at least twoanatomical structures, according to another exemplary embodiment of thepresent invention. Apparatus 300 includes a suture 302 having a firstend 304 and a second end 306, the suture 302 being constructed forpassage through anatomical structures in a manner to be describedsubsequently. Suture 302 may be formed from a wide variety of materials,for example, monofilament materials having minimal memory, includingpolypropylene or polyamide. Any appropriate diameter size may be used,for example, through 8-0. Other suture types and sizes are alsopossible, of course, and are equally contemplated by the presentinvention.

A needle 308 preferably is curved and is disposed at the first end 304of the suture 302. A sharp tip 310 of needle 308 enables easypenetration of various anatomical structures and enables the needle 308and the suture 302 to readily pass therethrough. The needle 308 may beattached to the suture 302 in various ways, for example, by swedging,preferably substantially matching the outer diameter of the needle 308and the suture 302 as closely as possible.

Apparatus 300 also includes a holding device 312 disposed at the secondend 306 of the suture 302. The holding device 312 includes first andsecond limbs 314, 316, according to the illustrated exemplaryembodiment, and preferably is of greater stiffness than the suture 302.The first limb 314 may be connected to suture 302 in a number of ways,for example, by swedging, preferably substantially matching the outsidediameter of the suture 302 and the holding device 312 as closely aspossible. The holding device 312 includes a staple structure comprisinga bendable material that preferably is soft and malleable enough tocrimp and hold its crimped position on the outside of an anastomosis.Such materials may include titanium or stainless steel. The holdingdevice 312 may be referred to as a staple, according to the illustratedembodiment, and the suture 302 and the needle 308 a delivery system forstaple 312.

FIG. 14 illustrates one of the many possible initial configurations ofholding device 312, i.e. the configuration the holding device 312 is inupon initial passage through the anatomical structures and/or at a pointin time beforehand. As will be described, the holding device 312 ismovable from the initial configuration to a holding configuration, inwhich holding device 312 holds the anatomical structures together.According to the illustrated exemplary embodiments, the holding device312 assumes the holding configuration when it is bent or crimped, asshown in FIG. 19 (further described below).

The holding device 312 preferably is substantially V-shaped orsubstantially U-shaped, as illustrated, but may assume a wide variety ofshapes to suit particular surgical situations and/or surgeon preference.For example, one of limbs 314, 316 may be straight and the other curved,or limbs 314, 316 may be collinear. The holding device 312 preferably isas smooth and round in cross-section as the needle 308. Further, thediameters of the needle 308, the suture 302, and the holding device 312preferably are substantially identical, especially the needle 308 andthe holding device 312, to avoid creating holes in the anatomicalstructures that are larger than the diameter of the staple 312. Suchholes likely would cause bleeding and/or leakage.

A method of using apparatus 300 is illustrated in FIGS. 15-19. First, asillustrated in FIG. 15, the needle 308 passes through anatomicalstructures 318, 320, which are, for example, vascular structures.Specifically, according to the illustrated exemplary embodiment, theneedle 308 passes through the edges 322, 324 of vascular structures 318,320. Then, as shown in FIG. 16, the needle 308 pulls suture 302 into andthrough both structures 318, 320. The staple 312 then is pulled intodesired proximity with structures 318, 320, as shown in FIGS. 17-19,such that it is engaged on both sides of the illustrated anastomosis andassociated lumen 326. According to one exemplary embodiment, traction isplaced on suture 302 to hook staple 312 into position.

As illustrated in FIG. 19 and as referenced earlier, the staple 312 thenis moved from its initial configuration to a holding or crimpedconfiguration 328, in which anatomical structures 318, 320 are joinedtogether to effect an anastomosis between them. The staple 312 creates asubstantially three hundred sixty-degree loop at the edge of theanastomosis, with crimped portion 330 outside lumen 321. A wide varietyof tools and/or mechanisms may be used to crimp the staple 312 into itsholding configuration, for example, in the manner of closure of avascular clip. The same tool, or an alternative tool, may then be usedto separate the staple 312 from the suture 302, for example, by cutting.

Thus, the staple 312 holds vascular structures 318, 320 together frominside the vascular structures, as well as from outside, unlike the manyprior art staples that secure opposed structures only externally. Thisachieves a number of advantages, as described above. Not only does abetter approximation result, but crimping a staple is simpler than tyingone or more knots and is also less likely traumatic on tissue. Stapleclosure with a single crimp provides less tension on an anastomosis, forexample, than a knot requiring several throws. Embodiments of theinvention are especially advantageous in minimally invasive surgicalsituations, as knot-tying with, for example, a knot pusher in aminimally invasive setting through a small port is particularly tediousand can require up to four or five throws to prevent slippage. Crimpinga staple through the port, as with embodiments of the invention, is farsimpler and eliminates much of the difficulty.

According to one exemplary embodiment, the surgeon achieves a preciseapproximation of the vascular or other structures with preferably alimited number of staples or other holding devices, and then completesthe anastomosis with biologic glue or laser techniques. The holdingdevices, for example, two or more in number, may be used to orient orline up the structures initially and thus used as a “pilot” for guidingthe completion of the anastomosis.

In the above described exemplary embodiment, the holding device 312 maybe coated with any of the above-described drugs, agents or compoundssuch as rapamycin to prevent or substantially reduce smooth muscle cellproliferation.

As described above, various drugs, agents or compounds may be locallydelivered via medical devices. For example, rapamycin and heparin may bedelivered by a stent to reduce restenosis, inflammation, andcoagulation. Various techniques for immobilizing the drugs, agents orcompounds are discussed above, however, maintaining the drugs, agents orcompounds on the medical devices during delivery and positioning iscritical to the success of the procedure or treatment. For example,removal of the drug, agent or compound coating during delivery of thestent can potentially cause failure of the device. For a self-expandingstent, the retraction of the restraining sheath may cause the drugs,agents or compounds to rub off the stent. For a balloon expandablestent, the expansion of the balloon may cause the drugs, agents orcompounds to simply delaminate from the stent through contact with theballoon or via expansion. Therefore, prevention of this potentialproblem is important to have a successful therapeutic medical device,such as a stent.

There are a number of approaches that may be utilized to substantiallyreduce the above-described concern. In one exemplary embodiment, alubricant or mold release agent may be utilized. The lubricant or moldrelease agent may comprise any suitable biocompatible lubriciouscoating. An exemplary lubricious coating may comprise silicone. In thisexemplary embodiment, a solution of the silicone base coating may beintroduced onto the balloon surface, onto the polymeric matrix, and/oronto the inner surface of the sheath of a self-expanding stent deliveryapparatus and allowed to air cure. Alternately, the silicone basedcoating may be incorporated into the polymeric matrix. It is importantto note, however, that any number of lubricious materials may beutilized, with the basic requirements being that the material bebiocompatible, that the material not interfere with theactions/effectiveness of the drugs, agents or compounds and that thematerial not interfere with the materials utilized to immobilize thedrugs, agents or compounds on the medical device. It is also importantto note that one or more, or all of the above-described approaches maybe utilized in combination.

Referring now to FIG. 20, there is illustrated a balloon 400 of aballoon catheter that may be utilized to expand a stent in situ. Asillustrated, the balloon 400 comprises a lubricious coating 402. Thelubricious coating 402 functions to minimize or substantially eliminatethe adhesion between the balloon 400 and the coating on the medicaldevice. In the exemplary embodiment described above, the lubriciouscoating 402 would minimize or substantially eliminate the adhesionbetween the balloon 400 and the heparin or rapamycin coating. Thelubricious coating 402 may be attached to and maintained on the balloon400 in any number of ways including but not limited to dipping,spraying, brushing or spin coating of the coating material from asolution or suspension followed by curing or solvent removal step asneeded.

Materials such as synthetic waxes, e.g. diethyleneglycol monostearate,hydrogenated castor oil, oleic acid, stearic acid, zinc stearate,calcium stearate, ethylenebis (stearamide), natural products such asparaffin wax, spermaceti wax, carnuba wax, sodium alginate, AscorbicAcid and flour, fluorinated compounds such as perfluoroalkanes,perfluorofatty acids and alcohol, synthetic polymers such as siliconese.g. polydimethylsiloxane, polytetrafluoroethylene, polyfluoroethers,polyalkylglycol e.g. polyethylene glycol waxes, and inorganic materialssuch as talc, kaolin, mica, and silica may be used to prepare thesecoatings. Vapor deposition polymerization e.g. parylene-C deposition, orRF-plasma polymerization of perfluoroalkenes and perfluoroalkanes canalso be used to prepare these lubricious coatings.

FIG. 21 illustrates a cross-section of a band 102 of the stent 100illustrated in FIG. 1. In this exemplary embodiment, the lubriciouscoating 500 is immobilized onto the outer surface of the polymericcoating. As described above, the drugs, agents or compounds may beincorporated into a polymeric matrix. The stent band 102 illustrated inFIG. 21 comprises a base coat 502 comprising a polymer and rapamycin anda top coat 504 or diffusion layer 504 also comprising a polymer. Thelubricious coating 500 is affixed to the top coat 502 by any suitablemeans, including but not limited to spraying, brushing, dipping or spincoating of the coating material from a solution or suspension with orwithout the polymers used to create the top coat, followed by curing orsolvent removal step as needed. Vapor deposition polymerization andRF-plasma polymerization may also be used to affix those lubriciouscoating materials that lend themselves to this deposition method, to thetop coating. In an alternate exemplary embodiment, the lubriciouscoating may be directly incorporated into the polymeric matrix.

If a self-expanding stent is utilized, the lubricious coating may beaffixed to the inner surface of the restraining sheath. FIG. 22illustrates a partial cross-sectional view of self-expanding stent 200within the lumen of a delivery apparatus sheath 14. As illustrated, alubricious coating 600 is affixed to the inner surfaces of the sheath14. Accordingly, upon deployment of the stent 200, the lubriciouscoating 600 preferably minimizes or substantially eliminates theadhesion between the sheath 14 and the drug, agent or compound coatedstent 200.

In an alternate approach, physical and/or chemical cross-linking methodsmay be applied to improve the bond strength between the polymericcoating containing the drugs, agents or compounds and the surface of themedical device or between the polymeric coating containing the drugs,agents or compounds and a primer. Alternately, other primers applied byeither traditional coating methods such as dip, spray or spin coating,or by RF-plasma polymerization may also be used to improve bondstrength. For example, as shown in FIG. 23, the bond strength can beimproved by first depositing a primer layer 700 such as vaporpolymerized parylene-C on the device surface, and then placing asecondary layer 702 which comprises a polymer that is similar inchemical composition to the one or more of the polymers that make up thedrug-containing matrix 704, e.g., polyethylene-co-vinyl acetate orpolybutyl methacrylate but has been modified to contain cross-linkingmoieties. This secondary layer 702 is then cross-linked to the primerafter exposure to ultra-violet light. It should be noted that anyonefamiliar with the art would recognize that a similar outcome could beachieved using cross-linking agents that are activated by heat with orwithout the presence of an activating agent. The drug-containing matrix704 is then layered onto the secondary layer 702 using a solvent thatswells, in part or wholly, the secondary layer 702. This promotes theentrainment of polymer chains from the matrix into the secondary layer702 and conversely from the secondary layer 702 into the drug-containingmatrix 704. Upon removal of the solvent from the coated layers, aninterpenetrating or interlocking network of the polymer chains is formedbetween the layers thereby increasing the adhesion strength betweenthem. A top coat 706 is used as described above.

A related difficulty occurs in medical devices such as stents. In thedrug-coated stents crimped state, some struts come into contact witheach other and when the stent is expanded, the motion causes thepolymeric coating comprising the drugs, agents or compounds to stick andstretch. This action may potentially cause the coating to separate fromthe stent in certain areas. The predominant mechanism of the coatingself-adhesion is believed to be due to mechanical forces. When thepolymer comes in contact with itself, its chains can tangle causing themechanical bond, similar to Velcro®. Certain polymers do not bond witheach other, for example, fluoropolymers. For other polymers, however,powders may be utilized. In other words, a powder may be applied to theone or more polymers incorporating the drugs, agents or other compoundson the surfaces of the medical device to reduce the mechanical bond. Anysuitable biocompatible material which does not interfere with the drugs,agents, compounds or materials utilized to immobilize the drugs, agentsor compounds onto the medical device may be utilized. For example, adusting with a water soluble powder may reduce the tackiness of thecoatings surface and this will prevent the polymer from sticking toitself thereby reducing the potential for delamination. The powdershould be water-soluble so that it does not present an emboli risk. Thepowder may comprise an anti-oxidant, such as vitamin C, or it maycomprise an anti-coagulant, such as aspirin or heparin. An advantage ofutilizing an anti-oxidant may be in the fact that the anti-oxidant maypreserve the other drugs, agents or compounds over longer periods oftime.

It is important to note that crystalline polymers are generally notsticky or tacky. Accordingly, if crystalline polymers are utilizedrather than amorphous polymers, then additional materials may not benecessary. It is also important to note that polymeric coatings withoutdrugs, agents and/or compounds may improve the operating characteristicsof the medical device. For example, the mechanical properties of themedical device may be improved by a polymeric coating, with or withoutdrugs, agents and/or compounds. A coated stent may have improvedflexibility and increased durability. In addition, the polymeric coatingmay substantially reduce or eliminate galvanic corrosion between thedifferent metals comprising the medical device. The same holds true foranastomosis devices.

As stated above, for a self-expanding stent, the retraction of therestraining sheath may cause the drugs, agents or compounds to rub offthe stent. Accordingly, in an alternate exemplary embodiment, the stentdelivery device may be modified to reduce the potential of rubbing offthe coating. This is especially important for long stents, for example,long rapamycin coated stents. In addition, there is also the potentialof damaging the stent itself when the delivery sheath is retractedduring stent deployment. Accordingly, the stent delivery device may bemodified to substantially reduce the forces acting on certain areas ofthe stent by distributing the forces to more areas of the stent. Thestent and stent delivery system described herein are intended to bemerely illustrative in nature and those skilled in the art willrecognize that the designs disclosed may be incorporated into any numberof stents and stent delivery systems.

FIGS. 35 and 36 illustrate an exemplary self-expanding stent deliveryapparatus 5010 in accordance with the present invention. Apparatus 5010comprises inner and outer coaxial tubes. The inner tube is called theshaft 5012 and the outer tube is called the sheath 5014. Aself-expanding stent 7000 is located within the sheath 5014, wherein thestent 7000 makes frictional contact with the sheath 5014 and the shaft5012 is disposed coaxially within a lumen of the stent 7000.

Shaft 5012 has proximal and distal ends 5016 and 5018 respectively. Theproximal end 5016 of the shaft 5012 has a Luer guidewire hub 5020attached thereto. As seen best from FIG. 44, the proximal end 5016 ofthe shaft 5012 is preferably a ground stainless steel hypotube. In oneexemplary embodiment, the hypotube is stainless steel and has a 0.042inch outside diameter at its proximal end and then tapers to a 0.036inch outside diameter at its distal end. The inside diameter of thehypotube is 0.032 inch throughout its length. The tapered outsidediameter is utilized to gradually change the stiffness of the hypotubealong its length. This change in the hypotube stiffness allows for amore rigid proximal end or handle end that is needed during stentdeployment. If the proximal end is not stiff enough, the hypotubesection extending beyond the Tuohy Borst valve described below couldbuckle as the deployment forces are transmitted. The distal end of thehypotube is more flexible allowing for better track-ability in tortuousvessels. The distal end of the hypotube also needs to be flexible tominimize the transition between the hypotube and the coil sectiondescribed below.

As will be described in greater detail below, shaft 5012 has a bodyportion 5022, wherein at least a section thereof is made from a flexiblecoiled member 5024, looking very much like a compressed or closed coilspring. Shaft 5012 also includes a distal portion 5026, distal to bodyportion 5022, which is preferably made from a coextrusion ofhigh-density polyethylene and Nylon®. The two portions 5022 and 5026 arejoined together by any number of means known to those of ordinary skillin the art including heat fusing, adhesive bonding, chemical bonding ormechanical attachment.

As best seen from FIG. 37, the distal portion 5026 of the shaft 5012 hasa distal tip 5028 attached thereto. Distal tip 5028 may be made from anynumber of suitable materials known in the art including polyamide,polyurethane, polytetrafluoroethylene, and polyethylene includingmulti-layer or single layer construction. The distal tip 5028 has aproximal end 5030 whose diameter is substantially the same as the outerdiameter of the sheath 5014 which is immediately adjacent thereto. Thedistal tip 5028 tapers to a smaller diameter from its proximal end 5030to its distal end 5032, wherein the distal end 5032 of the distal tip5028 has a diameter smaller than the inner diameter of the sheath 5014.

The stent delivery apparatus 5010 glides over a guide wire 8000 (shownin FIG. 35) during navigation to the stent deployment site. As usedherein, guidewire may also refer to similar guiding devices which have adistal protection apparatus incorporated herein. One preferred distalprotection device is disclosed in published PCT Application 98/33443,having an international filing date of Feb. 3, 1998. As discussed above,if the distal tip 5028 is too stiff it will overpower the guide wirepath and push the guide wire 8000 against the lumen wall and in somevery tortuous settings the stent delivery apparatus 5010 could prolapsethe wire. Overpowering of the wire and pushing of the apparatus againstthe lumen wall can prevent the device from reaching the target areabecause the guide wire will no longer be directing the device. Also, asthe apparatus is advanced and pushed against the lumen wall, debris fromthe lesion can be dislodged and travel upstream causing complications todistal vessel lumens. The distal tip 5028 is designed with an extremelyflexible leading edge and a gradual transition to a less flexibleportion. The distal tip 5028 may be hollow and may be made of any numberof suitable materials, including 40D Nylon®. Its flexibility may bechanged by gradually increasing the thickness of its cross-sectionaldiameter, whereby the diameter is thinnest at its distal end, and isthickest at its proximal end. That is, the cross-sectional diameter andwall thickness of the distal tip 5028 increases as you move in theproximal direction. This gives the distal end 5032 of the distal tip5028 the ability to be directed by the guidewire prior to the largerdiameter and thicker wall thickness, less flexible portion, of thedistal tip 5028 over-powering the guidewire. Over-powering the wire, asstated above, is when the apparatus, due to its stiffness, dictates thedirection of the device instead of following the wire.

The guidewire lumen 5034 has a diameter that is matched to hug therecommended size guide wire so that there is a slight frictionalengagement between the guidewire 8000 and the guidewire lumen 5034 ofdistal tip 5028. The distal tip 5028 has a rounded section 5036 betweenits distal portion 5032 and its proximal portion 5030. This helpsprevent the sheath 5014 from slipping distally over the distal tip 5028,and thereby exposing the squared edges of the sheath 5014 to the vessel,which could cause damage thereto. This improves the device's“pushability.” As the distal tip 5028 encounters resistance it does notallow the sheath 5014 to ride over it thereby exposing the sheath's 5014square cut edge. Instead the sheath 5014 contacts the rounded section5036 of the distal tip 5028 and thus transmits the forces applied to thedistal tip 5028. The distal tip 5028 also has a proximally taperedsection 5038 which helps guide the distal tip 5028 through the deployedstent 7000 without providing a sharp edge that could grab or hang up ona stent strut end or other irregularity in the lumen inner diameter.

Attached to distal portion 5026 of shaft 5012 is a stop 5040, which isproximal to the distal tip 5028 and stent 7000. Stop 5040 may be madefrom any number of suitable materials known in the art, includingstainless steel, and is even more preferably made from a highlyradio-opaque material such as platinum, gold tantalum, or radio-opaquefilled polymer. The stop 5040 may be attached to shaft 5012 by anysuitable means, including mechanical or adhesive bonding, or by anyother means known to those skilled in the art. Preferably, the diameterof stop 5040 is large enough to make sufficient contact with the loadedstent 7000 without making frictional contact with the sheath 5014. Aswill be explained subsequently, the stop 5040 helps to “push” the stent7000 or maintain its relative position during deployment, by preventingthe stent 7000 from migrating proximally within the sheath 5014 duringretraction of the sheath 5014 for stent deployment. The radio-opaquestop 5040 also aides in positioning the stent 7000 within the targetlesion area during deployment within a vessel, as is described below.

A stent bed 5042 is defined as being that portion of the shaft 5012between the distal tip 5028 and the stop 5040 (FIG. 36). The stent bed5042 and the stent 7000 are coaxial so that the distal portion 5026 ofthe shaft 5012 comprising the stent bed 5042 is located within the lumenof stent 7000. The stent bed 5042 makes minimal contact with the stent7000 because of the space which exists between the shaft 5012 and thesheath 5014. As the stent 7000 is subjected to temperatures at theaustenite phase transformation it attempts to recover to its programmedshape by moving outwardly in a radial direction within the sheath 5014.The sheath 5014 constrains the stent 7000 as will be explained in detailsubsequently. Distal to the distal end of the loaded stent 7000 attachedto the shaft 5012 is a radio-opaque marker 5044 which may be made ofplatinum, iridium coated platinum, gold tantalum, stainless steel,radio-opaque filled polymer or any other suitable material known in theart.

As seen from FIGS. 36, 37 and 44, the body portion 5022 of the shaft5012 is made from a flexible coiled member 5024, similar to a closedcoil or compressed spring. During deployment of the stent 7000, thetransmission of compressive forces from the stop 5040 to the Luerguidewire hub 5020 is an important factor in deployment accuracy. A morecompressive shaft 5012 results in a less accurate deployment because thecompression of the shaft 5012 is not taken into account when visualizingthe stent 7000 under fluoroscopic imaging. However, a less compressiveshaft 5012 usually means less flexibility, which would reduce theability of the apparatus 5010 to navigate through tortuous vessels. Acoiled assembly allows both flexibility and resistance to compression.When the apparatus 5010 is being navigated through the arteries, theshaft 5012 is not in compression and therefore the coiled member 5024 isfree to bend with the delivery path. As one deploys the stent 7000,tension is applied to the sheath 5014 as the sheath 5014 is retractedover the encapsulated stent 7000. Because the stent 7000 isself-expanding it is in contact with the sheath 5014 and the forces aretransferred along the stent 7000 and to the stop 5040 of the shaft 5012.This results in the shaft 5012 being under compressive forces. When thishappens, the flexible coiled member 5024, no gaps between the coilmembers, transfers the compressive force from one coil to the next.

The flexible coiled member 5024 further includes a covering 5046 thatfits over the flexible coiled member 5024 to help resist buckling of thecoiled member 5024 in both bending and compressive modes. The covering5046 is an extruded polymer tube and is preferably a soft material thatcan elongate slightly to accommodate bending of the flexible coiledmember 5024, but does not allow the coils to ride over each other.Covering 5046 may be made from any number of suitable materialsincluding coextrusions of Nylon® and high-density polyethylene,polyurethane, polyamide, polytetrafluoroethylene, etc. The extrusion isalso attached to the stop 5040. Flexible coiled member 5024 may be madeof any number of materials known in the art including stainless steel,Nitinol, and rigid polymers. In one exemplary embodiment, flexiblecoiled member 5024 is made from a 0.003 inch thick by 0.010 inch widestainless steel ribbon wire. The wire may be round, or more preferablyflat to reduce the profile of the flexible coiled member 5024.

Sheath 5014 is preferably a polymeric catheter and has a proximal end5048 terminating at a sheath hub 5050 (FIG. 35). Sheath 5014 also has adistal end 5052 which terminates at the proximal end 5030 of distal tip5028 of the shaft 5012, when the stent 7000 is in an un-deployedposition as shown in FIG. 36. The distal end 5052 of sheath 5014includes a radio-opaque marker band 5054 disposed along its outersurface (FIG. 35). As will be explained below, the stent 7000 is fullydeployed when the marker band 5054 is proximal to radio-opaque stop5040, thus indicating to the physician that it is now safe to remove thedelivery apparatus 5010 from the body.

As detailed in FIG. 36, the distal end 5052 of sheath 5014 includes anenlarged section 5056. Enlarged section 5056 has larger inside andoutside diameters than the inside and outside diameters of the sheath5014 proximal to enlarged section 5056. Enlarged section 5056 houses thepre-loaded stent 7000, the stop 5040 and the stent bed 5042. The outersheath 5014 tapers proximally at the proximal end of enlarged section5056 to a smaller size diameter. This design is more fully set forth inco-pending U.S. application Ser. No. 09/243,750 filed on Feb. 3, 1999,which is hereby incorporated herein by reference. One particularadvantage to the reduction in the size of the outer diameter of sheath5014 proximal to enlarged section 5056 is in an increase in theclearance between the delivery apparatus 5010 and the guiding catheteror sheath that the delivery apparatus 5010 is placed through. Usingfluoroscopy, the physician will view an image of the target site withinthe vessel, before and after deployment of the stent, by injecting aradio-opaque solution through the guiding catheter or sheath with thedelivery apparatus 5010 placed within the guiding catheter. Because theclearance between the sheath 5014, and the guiding catheter is increasedby tapering or reducing the outer diameter of the sheath 5014 proximalto enlarged section 5056, higher injection rates may be achieved,resulting in better images of the target site for the physician. Thetapering of sheath 5014 provides for higher injection rates ofradio-opaque fluid, both before and after deployment of the stent.

A problem encountered with earlier self-expanding stent delivery systemsis that of the stent becoming embedded within the sheath in which it isdisposed. Referring to FIG. 45, there is illustrated a sheathconstruction which may be effectively utilized to substantially preventthe stent from becoming embedded in the sheath as well as provide otherbenefits as described in detail below. As illustrated, the sheath 5014comprises a composite structure of at least two layers and preferablythree layers. The outer layer 5060 may be formed from any suitablebiocompatible material. Preferably, the outer layer 5060 is formed froma lubricious material for ease of insertion and removal of the sheath5014. In a preferred embodiment, the outer layer 5060 comprises apolymeric material such as Nylon®. The inner layer 5062 may also beformed from any suitable biocompatible material. For example, the innerlayer 5062 may be formed from any number of polymers includingpolyethylene, polyamide or polytetrafluoroethylene. In a preferredembodiment, the inner layer 5062 comprises polytetrafluoroethylene.Polytetrafluoroethylene is also a lubricious material which makes stentdelivery easier, thereby preventing damage to the stent 7000. The innerlayer 5062 may also be coated with another material to increase thelubricity thereof for facilitating stent deployment. Any number ofsuitable biocompatible materials may be utilized. In an exemplaryembodiment, silicone based coatings may be utilized. Essentially, asolution of the silicone based coating may be injected through theapparatus and allowed to cure at room temperature. The amount ofsilicone based coating utilized should be minimized to preventtransference of the coating to the stent 7000. Sandwiched between theouter and inner layers 5060 and 5062, respectively, is a wirereinforcement layer 5064. The wire reinforcement layer 5064 may take onany number of configurations. In the exemplary embodiment, the wirereinforcement layer 5064 comprises a simple under and over weave orbraiding pattern. The wire used to form the wire reinforcement layer5064 may comprise any suitable material and any suitable cross-sectionalshape. In the illustrated exemplary embodiment, the wire forming thewire reinforcement layer 5064 comprises stainless steel and has asubstantially circular cross-section. In order to function for itsintended purpose, as described in detail below, the wire has a diameterof 0.002 inches.

The three layers 5060, 5062, and 5064 comprising the sheath 5014collectively enhance stent deployment. The outer layer 5060 facilitatesinsertion and removal of the entire apparatus 5010. The inner layer 5062and the wire reinforcement layer 5064 function to prevent the stent 7000from becoming embedded in the sheath 5014. Self-expanding stents such asthe stent 7000 of the present invention tend to expand to theirprogrammed diameter at a given temperature. As the stent attempts toundergo expansion, it exerts a radially outward directed force and maybecome embedded in the sheath 5014 restraining it from expanding.Accordingly, the wire reinforcing layer 5064 provides radial or hoopstrength to the inner layer 5062 thereby creating sufficient resistanceto the outwardly directed radial force of the stent 7000 within thesheath 5014. The inner layer 5062, also as discussed above, provides alower coefficient of friction surface to reduce the forces required todeploy the stent 7000 (typically in the range from about five to eightpounds). The wire reinforcement layer 5064 also provides tensilestrength to the sheath 5014. In other words, the wire reinforcementlayer 5064 provides the sheath 5014 with better pushability, i.e., theability to transmit a force applied by the physician at a proximallocation on the sheath 5014 to the distal tip 5028, which aids innavigation across tight stenotic lesions within the vasculature. Wirereinforcement layer 5064 also provides the sheath 5014 with betterresistance to elongation and necking as a result of tensile loadingduring sheath retraction for stent deployment.

The sheath 5014 may comprise all three layers along its entire length oronly in certain sections, for example, along the length of the stent7000. In a preferred embodiment, the sheath 5014 comprises all threelayers along its entire length.

Prior art self-expanding stent delivery systems did not utilize wirereinforcement layers. Because the size of typical self-expanding stentsis relatively large, as compared to balloon expandable coronary stents,the diameter or profile of the delivery devices therefore had to belarge as well. However, it is always advantageous to have deliverysystems which are as small as possible. This is desirable so that thedevices can reach into smaller vessels and so that less trauma is causedto the patient. However, as stated above, the advantages of a thinreinforcing layer in a stent delivery apparatus outweighs thedisadvantages of slightly increased profile.

In order to minimize the impact of the wire reinforcement layer on theprofile of the apparatus 5010, the configuration of the wirereinforcement layer 5064 may be modified. For example, this may beaccomplished in a number of ways, including changing the pitch of thebraid, changing the shape of the wire, changing the wire diameter and/orchanging the number of wires utilized. In a preferred embodiment, thewire utilized to form the wire reinforcement layer comprises asubstantially rectangular cross-section as illustrated in FIG. 46. Inutilizing a substantially rectangular cross-section wire, the strengthfeatures of the reinforcement layer 5064 may be maintained with asignificant reduction in the profile of the delivery apparatus. In thispreferred embodiment, the rectangular cross-section wire has a width of0.003 inches and a height of 0.001 inches. Accordingly, braiding thewire in a similar manner to FIG. 45, results in a fifty percent decreasein the thickness of the wire reinforcement layer 5064 while maintainingthe same beneficial characteristics as the 0.002 round wire. The flatwire may comprise any suitable material, and preferably comprisesstainless steel.

In another alternate exemplary embodiment, the sheath of the deliverysystem may comprise an inner layer or coating on its inner surface whichsubstantially prevents the stent from becoming embedded therein whileincreasing the lubricity thereof. This inner layer or coating may beutilized with the sheaths illustrated in FIGS. 45 and 46 or as analternative means to decrease the stent deployment forces. Given thethinness of the coating, as described in more detail below, the overallprofile of the delivery system will be minimally impacted if at all. Inaddition to increasing the strength of the sheath and making it morelubricious, the coating is extremely biocompatible which is importantsince it does make contact with blood, albeit at least temporarily.

Essentially, in the exemplary embodiment, a hard and lubricious coatingis applied to or affixed to the inner surface of the sheath of theself-expanding delivery system. The coating provides a number ofadvantages over currently utilized self-expanding stent deliverysystems. For example, the coating provides a hard surface against whichthe stent exerts a radially outward directed force. As described above,self-expanding stents have a constant outward force of expansion whenloaded into the delivery system. This constant and relatively highradially outward directed force can force the polymeric materials thatcomprise the sheath of the delivery system to creep and allow the stentto become embedded into the polymer surface. As stent platforms aredeveloped with larger diameter stents and subsequently higher radiallyoutward directed forces, the occurrence of this phenomenon willincrease. Consequently, embedding increases the force required to deploythe stent because it causes mechanical resistance to the movement of thestent inside the delivery system, thereby preventing accurate deploymentand causing potential damage to the stent. In addition, the coating islubricious, i.e. it has a low coefficient of friction. A lubriciouscoating, as stated above, functions to further reduce the force requiredto deploy the stent, thereby increasing the facility by which the stentsare delivered and deployed by physicians. This is especially importantwith respect to newer larger diameter stent designs and/or drug/polymercoated stent designs that have either increased radial forces, increasedprofile or increased overall diameter. A lubricious coating isparticularly advantageous with respect to drug/polymer coated stents.Accordingly, the coating functions to prevent the stent from embeddingin the sheath of the delivery system prior to deployment and reducingthe friction between the sheath and the stent, both of which will reducethe deployment forces.

Various drugs, agents or compounds may be locally delivered via medicaldevices such as stents. For example, rapamycin and/or heparin may bedelivered by a stent to reduce restenosis, inflammation and coagulation.Various techniques for immobilizing the drugs, agents or compounds ontothe stent are known; however, maintaining the drugs, agents or compoundson the stent during delivery and positioning is critical to the successof the procedure or treatment. For example, removal of the drug, agentor compound during delivery of the stent can potentially cause failureof the device. For a self-expanding stent, the retraction of therestraining sheath may cause the drugs, agents or compounds to rub offthe stent. Therefore, prevention of this potential problem is importantto have successful therapeutic medical devices such as stents.

FIG. 47 illustrates a partial cross-sectional view of the shaft andmodified sheath of the stent delivery system in accordance with anexemplary embodiment of the present invention. As shown, a coating orlayer of material 5070 is affixed or otherwise attached to the innercircumference of the sheath 5014. As stated above, the coating or layerof material 5070 comprises a hard and lubricious substance. In apreferred embodiment, the coating 5070 comprises pyrolytic carbon.Pyrolytic carbon is a well-known substance that is utilized in a widevariety of implantable medical prostheses and is most commonly utilizedin cardiac valves, as it combines high strength with excellent tissueand blood compatibility.

Pyrolytic carbon's usefulness in the implantable medical device area isa result of its unique combination of physical and chemicalcharacteristics, including chemical inertness, isotrophy, low weight,compactness and elasticity. Pyrolytic carbon belongs to a specificfamily of turbostratic carbons which are similar to the structure ofgraphite. In graphite, the carbon atoms are covalently bonded in planarhexagonal arrays that are stacked in layers with relatively weakinterlayer bonding. In turbostratic carbons, the stacking sequence isdisordered and distortions may exist within each of the layers. Thesestructural distortions in the layers are responsible for the superiorductility and durability of pyrolytic carbon. Essentially, themicrostructure of pyrolytic carbon makes the material durable, strongand wear resistant. In addition, pyrolytic carbon is highlythromboresistant and has inherent cellular biocompatability with bloodand soft tissue.

The pyrolytic carbon layer 5070 may be deposited along the entire lengthof the sheath 5014 or only in proximity to the stent bed 5042,illustrated in FIGS. 36 and 37. In a preferred embodiment, the pyrolyticcarbon layer 5070 is affixed to the sheath 5014 in the region of thestent bed 5042. The pyrolytic carbon layer 5070 may be deposited oraffixed to the inner circumference utilizing any number of knowntechniques that are compatible or usable with the polymeric materialscomprising the sheath 5014. The thickness of the pyrolytic carbon layer5070 is selected such that it prevents or substantially reduces thepossibility of the stent becoming embedded in the sheath 5014 withoutdecreasing the flexibility of the sheath 5014 or increasing the profileof the self-expanding stent delivery system. As described above, it isimportant that the sheath be both flexible and pushable to navigatetortuous pathways within the body. In addition, it is always desirableto reduce the profile of percutaneously delivered devices.

As stated above, pyrolytic carbon surfaces are recognized asbiocompatible, especially with respect to blood contact applications.This is, however, only a minor benefit in terms of stent deliveryapplications because the location of the pyrolytic carbon layer 5070within the sheath 5014 is only minimally exposed to blood and is onlywithin the body for a duration sufficient to deliver a stent.

The pyrolytic carbon layer 5070 may be affixed to the lumen of thesheath in any number of ways as mentioned above. In one exemplaryembodiment, the pyrolytic carbon layer 5070 may be directly affixed tothe lumen of the sheath 5014. In another exemplary embodiment, thepyrolytic carbon layer 5070 may be indirectly applied to the lumen ofthe sheath 5014 by first applying it to a variety of substrates, alsoutilizing any number of known techniques. Regardless of whether thepyrolytic carbon layer 5070 is deposited directly onto the sheath 5014or first onto a substrate, any number of known techniques may beutilized, for example, chemical vapor deposition. In chemical vapordeposition, the carbon material is deposited from gaseous hydrocarboncompounds on suitable underlying substrates, e.g. carbon materials,metals, ceramics as well as other materials, at temperatures rangingfrom about 1000K to about 2500K. At these temperatures, one canunderstand the need to possibly utilize substrates. Any suitablebiocompatible, durable and flexible substrate may be utilized and thenaffixed to the lumen of the sheath 5014 utilizing well-known techniquessuch as adhesives. As stated above, profile and flexibility areimportant design characteristics; accordingly, the type of substratematerial chosen and/or its thickness should be considered. It isimportant to note that a wide range of microstructures, e.g. isotropic,lamellor, substrate-nucleated and a varied content of remaining hydrogencan occur in pyrolytic carbons, depending on the deposition conditions,including temperature, type, concentration and flow rates of the sourcegas and surface area of the underlying substrate.

Other techniques which may be utilized to affix the pyrolytic carbonlayer 5070 directly onto the sheath 5014 or onto a substrate includepulsed laser ablation deposition, radio frequency plasma modification,physical vapor deposition as well as other known techniques. In additionto pyrolytic carbon, other materials that might be beneficial inproviding similar properties include diamond-like carbon coatings,silane/silicon glass like surfaces and thin ceramic coatings such asalumina, hydroxyapatite and titania.

In an alternate exemplary embodiment, the pyrolytic carbon coating maybe applied with a controlled finite porosity as briefly described above.This controlled finite porosity provides two distinct advantages. First,the porosity may serve to reduce the contact surface area if the stentwith the pyrolytic carbon coating 5070, thereby reducing the frictionbetween the stent and the inner lumen of the sheath 5014. Second,lubricious materials such as biocompatible oils, waxes and powders couldbe infused or impregnated within the porous surface of the coatingthereby providing a reservoir of lubricious material further reducingthe frictional coefficient.

FIGS. 35 and 36 show the stent 7000 as being in its fully un-deployedposition. This is the position the stent is in when the apparatus 5010is inserted into the vasculature and its distal end is navigated to atarget site. Stent 7000 is disposed around the stent bed 5042 and at thedistal end 5052 of sheath 5014. The distal tip 5028 of the shaft 5012 isdistal to the distal end 5052 of the sheath 5014. The stent 7000 is in acompressed state and makes frictional contact with the inner surface ofthe sheath 5014.

When being inserted into a patient, sheath 5014 and shaft 5012 arelocked together at their proximal ends by a Tuohy Borst valve 5058. Thisprevents any sliding movement between the shaft 5012 and sheath 5014,which could result in a premature deployment or partial deployment ofthe stent 7000. When the stent 100 reaches its target site and is readyfor deployment, the Tuohy Borst valve 5058 is opened so that the sheath5014 and shaft 5012 are no longer locked together.

The method under which delivery apparatus 5010 deploys stent 7000 maybest be described by referring to FIGS. 39-43. In FIG. 39, the deliveryapparatus 5010 has been inserted into a vessel 9000 so that the stentbed 5042 is at a target diseased site. Once the physician determinesthat the radio-opaque marker band 5054 and stop 5040 on shaft 5012indicating the ends of stent 7000 are sufficiently placed about thetarget disease site, the physician would open Tuohy Borst valve 5058.The physician would then grasp the Luer guidewire hub 5020 of shaft 5012so as to hold shaft 5012 in a fixed position. Thereafter, the physicianwould grasp the Tuohy Borst valve 5058, attached proximally to sheath5014, and slide it proximal, relative to the shaft 5012 as shown inFIGS. 40 and 41. Stop 5040 prevents the stent 7000 from sliding backwith sheath 5014, so that as the sheath 5014 is moved back, the stent7000 is effectively “pushed” out of the distal end 5052 of the sheath5014, or held in position relative to the target site. Stent 7000 shouldbe deployed in a distal to proximal direction to minimize the potentialfor creating emboli with the diseased vessel 9000. Stent deployment iscomplete when the radio-opaque band 5054 on the sheath 5014 is proximalto radio-opaque stop 5040, as shown in FIG. 42. The apparatus 5010 cannow be withdrawn through stent 7000 and removed from the patient.

FIGS. 36 and 43 show a preferred embodiment of a stent 7000, which maybe used in conjunction with the present invention. Stent 7000 is shownin its unexpanded compressed state, before it is deployed, in FIG. 36.Stent 7000 is preferably made from a superelastic alloy such as Nitinol.Most preferably, the stent 7000 is made from an alloy comprising fromabout 50.5 percent (as used herein these percentages refer to atomicpercentages) Ni to about 60 percent Ni, and most preferably about 55percent Ni, with the remainder of the alloy Ti. Preferably, the stent7000 is such that it is superelastic at body temperature, and preferablyhas an Af in the range from about twenty-one degrees C. to aboutthirty-seven degrees C. The superelastic design of the stent makes itcrush recoverable which, as discussed above, can be used as a stent orframe for any number of vascular devices for different applications.

Stent 7000 is a tubular member having front and back open ends alongitudinal axis extending there between. The tubular member has afirst smaller diameter, FIG. 30, for insertion into a patient andnavigation through the vessels, and a second larger diameter fordeployment into the target area of a vessel. The tubular member is madefrom a plurality of adjacent hoops 7002 extending between the front andback ends. The hoops 7002 include a plurality of longitudinal struts7004 and a plurality of loops 7006 connecting adjacent struts, whereinadjacent struts are connected at opposite ends so as to form asubstantially S or Z shape pattern. Stent 7000 further includes aplurality of curved bridges 7008, which connect adjacent hoops 7002.Bridges 7008 connect adjacent struts together at bridge to loopconnection points which are offset from the center of a loop.

The above described geometry helps to better distribute strainthroughout the stent, prevents metal to metal contact when the stent isbent, and minimizes the opening size between the features, struts, loopsand bridges. The number of and nature of the design of the struts, loopsand bridges are important factors when determining the workingproperties and fatigue life properties of the stent. Preferably, eachhoop has between twenty-four to thirty-six or more struts. Preferablythe stent has a ratio of number of struts per hoop to strut length (ininches) which is greater than two hundred. The length of a strut ismeasured in its compressed state parallel to the longitudinal axis ofthe stent.

In trying to minimize the maximum strain experienced by features, thestent utilizes structural geometries which distribute strain to areas ofthe stent which are less susceptible to failure than others. Forexample, one vulnerable area of the stent is the inside radius of theconnecting loops. The connecting loops undergo the most deformation ofall the stent features. The inside radius of the loop would normally bethe area with the highest level of strain on the stent. This area isalso critical in that it is usually the smallest radius on the stent.Stress concentrations are generally controlled or minimized bymaintaining the largest radii possible. Similarly, we want to minimizelocal strain concentrations on the bridge and bridge to loop connectionpoints. One way to accomplish this is to utilize the largest possibleradii while maintaining feature widths, which are consistent withapplied forces. Another consideration is to minimize the maximum openarea of the stent. Efficient utilization of the original tube from whichthe stent is cut increases stent strength and it's ability to trapembolic material.

As set forth above, stents coated with combinations of polymers anddrugs, agents and/or compounds may potentially increase the forcesacting on the stent during stent deployment. This increase in forces mayin turn damage the stent. For example, as described above, duringdeployment, the stent is forced against a stop to overcome the force ofsliding the outer sheath back. With a longer stent, e.g. greater than200 mm, the forces exerted on the end of the stent during sheathretraction may be excessive and could potentially cause damage to theend of the stent or to other sections of the stent. Accordingly, a stentdelivery device which distributes the forces over a greater area of thestent would be beneficial.

FIG. 48 illustrates a modified shaft 5012 of the stent delivery section.In this exemplary embodiment, the shaft 5012 comprises a plurality ofraised sections 5200. The raised sections 5200 may comprise any suitablesize and geometry and may be formed in any suitable manner. The raisedsections 5200 may comprise any suitable material, including the materialforming the shaft 5012. The number of raised sections 5200 may also bevaried. Essentially, the raised sections 5200 may occupy the open spacesbetween the stent 7000 elements. All of the spaces may be filled orselect spaces may be filled. In other words, the pattern and number ofraised sections 5200 is preferably determined by the stent design. Inthe illustrated embodiment, the raised sections or protrusions 5200 arearranged such that they occupy the spaces formed between adjacent loops7006 on adjacent hoops 7002 and between the bridges 7008.

The raised sections 5200 may be formed in any number of ways. Forexample, the raised sections 5200 may be formed using a heated clamshellmold or a waffle iron heated die approach. Either method allows for thelow cost mass production of inner shafts comprising protrusions.

The size, shape and pattern of the raised sections 5200 may be modifiedto accommodate any stent design. The height of each of the raisedsections 5200 is preferably large enough to compensate for the slightgap that exists between the inner shaft 5012 and the outer sheath 5014.The height, H, of the raised sections or protrusions 5200 on the shaft5012 should preferably be, at a minimum, greater than the difference inradius between the outside diameter of the shaft 5012, IM(r), and theinside diameter of the sheath 5014, OM(r), minus the wall thickness ofthe device or stent 7000, WT. The equation representing thisrelationship is given byH>(OM(r)−IM(r))−WT.For example, if the shaft 5012 has an outside diameter of 0.08 inches,the sheath 5014 has an inside diameter of 0.1 inches, and the wallthickness of the stent 7000 is 0.008 inches, then the height of theraised sections or protrusions 5200 is

${H > {\left( {\frac{0.100}{2} - \frac{0.080}{2}} \right) - 0.008}},$orH>0.002 inches.

It is important to note that the height of the raised sections 5200should preferably be less than the difference between the radius of thesheath and the radius of the shaft unless the protrusions 5200 arecompressible.

Although each raised section 5200 is small, the number of raisedsections 5200 may be large and each of the raised sections 5200 apply asmall amount of force to different parts of the stent 7002, therebydistributing the force to deploy the stent 7000 and preventing damage tothe stent 7000 particularly at its proximal end. The raised sections5200 also protect the stent 7000 during loading of the stent 7000 intothe delivery system. Essentially, the same forces that act on the stent7000 during deployment act on the stent 7000 during loading. Thelongitudinal flexibility of the stent necessitates that as little forceas possible is placed on the stent as it is released or deployed toensure repeatable foreshortening and accurate placement. Essentially, itis preferable that longitudinal movement of the stent 7000 be eliminatedor substantially reduced during deployment thereby eliminating orsubstantially reducing compression of the stent. Without the raisedsections 5200, as the stent 7000 is being deployed, the compressiveforces will compress the delivery system as well as the stent 7000. Thiscompressive energy will be released upon deployment, reducing thechances of accurate placement of the stent 7000 and contributing to thepossibility of stent “jumping.” With the raised sections 5200, the stent7000 is less likely to move, thereby eliminating or substantiallyreducing compression.

In an alternate exemplary embodiment, once the stent is positioned onthe shaft of the delivery device, the stent may be heated and externallypressurized to make a mirror-like imprint in the inner shaft of thedelivery system. The imprint provides a three-dimensional surface whichallows the stent to maintain its position as the sheath is retracted.The three-dimensional imprint may be made using heat alone, pressurealone or with a separate device.

Any of the above-described medical devices may be utilized for the localdelivery of drugs, agents and/or compounds to other areas, notimmediately around the device itself. In order to avoid the potentialcomplications associated with systemic drug delivery, the medicaldevices of the present invention may be utilized to deliver therapeuticagents to areas adjacent to the medical device. For example, a rapamycincoated stent may deliver the rapamycin to the tissues surrounding thestent as well as areas upstream of the stent and downstream of thestent. The degree of tissue penetration depends on a number of factors,including the drug, agent or compound, the concentrations of the drugand the release rate of the agent. The same holds true for coatedanastomosis devices.

The drug, agent and/or compound/carrier or vehicle compositionsdescribed above may be formulated in a number of ways. For example, theymay be formulated utilizing additional components or constituents,including a variety of excipient agents and/or formulary components toaffect manufacturability, coating integrity, sterilizability, drugstability, and drug release rate. Within exemplary embodiments of thepresent invention, excipient agents and/or formulary components may beadded to achieve both fast-release and sustained-release drug elutionprofiles. Such excipient agents may include salts and/or inorganiccompounds such as acids/bases or buffer components, anti-oxidants,surfactants, polypeptides, proteins, carbohydrates including sucrose,glucose or dextrose, chelating agents such as EDTA, glutathione or otherexcipients or agents.

It is important to note that any of the above-described medical devicesmay be coated with coatings that comprise drugs, agents or compounds orsimply with coatings that contain no drugs, agents or compounds. Inaddition, the entire medical device may be coated or only a portion ofthe device may be coated. The coating may be uniform or non-uniform. Thecoating may be discontinuous.

As described above, any number of drugs, agents and/or compounds may belocally delivered via any number of medical devices. For example, stentsand anastomosis devices may incorporate coatings comprising drugs,agents and/or compounds to treat various disease states and reactions bythe body as described in detail above. Other devices which may be coatedwith or otherwise incorporate therapeutic dosages of drugs, agentsand/or compounds include stent-grafts, which are briefly describedabove, and devices utilizing stent-grafts, such as devices for treatingabdominal aortic aneurysms as well as other aneurysms, e.g. thoracicaorta aneurysms.

Stent-grafts, as the name implies, comprise a stent and a graft materialattached thereto. FIG. 24 illustrates an exemplary stent-graft 800. Thestent-graft 800 may comprise any type of stent and any type of graftmaterial as described in detail subsequently. In the illustratedexemplary embodiment, the stent 802 is a self-expanding device. Atypical self-expanding stent comprises an expandable lattice or networkof interconnected struts. In preferred embodiments of the invention, thelattice is fabricated, e.g. laser cut, from an integral tube ofmaterial.

In accordance with the present invention, the stent may be variouslyconfigured. For example, the stent may be configured with struts or thelike that form repeating geometric shapes. One skilled in the art willreadily recognize that a stent may be configured or adapted to includecertain features and/or to perform a certain function(s), and thatalternate designs may be used to promote that feature or function.

In the exemplary embodiment of the invention illustrated in FIG. 24, thematrix or struts of stent 802 may be configured into at least two hoops804, each hoop 804 comprising a number of struts 806 formed into adiamond shape, having approximately nine diamonds. The stent 802 mayfurther include a zigzag shaped ring 808 for connecting adjacent hoopsto one another. The zigzag shaped rings 808 may be formed from a numberof alternating struts 810, wherein each ring has fifty-four struts.

An inner or outer surface of the stent 802 may be covered by or supporta graft material. Graft material 812 may be made from any number ofmaterials known to those skilled in the art, including woven or otherconfigurations of polyester, Dacron®, Teflon®, polyurethane porouspolyurethane, silicone, polyethylene, terephthalate, expandedpolytetrafluoroethylene (ePTFE) and blends of various materials.

The graft material 812 may be variously configured, preferably toachieve predetermined mechanical properties. For example, the graftmaterial may incorporate a single or multiple weaving and/or pleatingpatterns, or may be pleated or unpleated. For example, the graftmaterial may be configured into a plain weave, a satin weave, includelongitudinal pleats, interrupted pleats, annular or helical pleats,radially oriented pleats, or combinations thereof. Alternately, thegraft material may be knitted or braided. In the embodiments of theinvention in which the graft material is pleated, the pleats may becontinuous or discontinuous. Also, the pleats may be orientedlongitudinally, circumferentially, or combinations thereof.

As illustrated in FIG. 24, the graft material 812 may include aplurality of longitudinal pleats 814 extending along its surface,generally parallel to the longitudinal axis of the stent-graft 800. Thepleats 814 allow the stent-graft 800 to collapse around its center, muchas it would be when it is delivered into a patient. This provides arelatively low profile delivery system, and provides for a controlledand consistent deployment therefrom. It is believed that thisconfiguration minimizes wrinkling and other geometric irregularities.Upon subsequent expansion, the stent-graft 800 assumes its naturalcylindrical shape, and the pleats 814 uniformly and symmetrically open.

In addition, the pleats 814 help facilitate stent-graft manufacture, inthat they indicate the direction parallel to the longitudinal axis,allowing stent to graft attachment along these lines, and therebyinhibiting accidental twisting of the graft relative to the stent afterattachment. The force required to push the stent-graft 800 out of thedelivery system may also be reduced, in that only the pleated edges ofthe graft make frictional contact with the inner surface of the deliverysystem. One further advantage of the pleats 814 is that blood tends tocoagulate generally uniformly in the troughs of the pleats 814,discouraging asymmetric or large clot formation on the graft surface,thereby reducing embolus risk.

As shown in FIG. 24, the graft material 812 may also include one ormore, and preferably a plurality of, radially oriented pleatinterruptions 816. The pleat interruptions 816 are typicallysubstantially circular and are oriented perpendicular to longitudinalaxis. Pleat interruptions 816 allow the graft and stent to bend betterat selective points. This design provides for a graft material that hasgood crimpability and improved kink resistance.

The foregoing graft materials may be braided, knitted or woven, and maybe warp or weft knitted. If the material is warp knitted, it may beprovided with a velour, or towel like surface; which is believed tospeed the formation of blood clots, thereby promoting the integration ofa stent-graft or stent-graft component into the surrounding cellularstructure.

A graft material may be attached to a stent or to another graft materialby any number of structures or methods known to those skilled in theart, including adhesives, such as polyurethane glue; a plurality ofconventional sutures of polyvinylidene fluoride, polypropylene, Dacron®,or any other suitable material; ultrasonic welding; mechanicalinterference fit; and staples.

The stent 802 and/or graft material 812 may be coated with any of theabove-described drugs, agents and/or compounds. In one exemplaryembodiment, rapamycin may be affixed to at least a portion of the graftmaterial 812 utilizing any of the materials and processes describedabove. In another exemplary embodiment, rapamycin may be affixed to atleast a portion of the graft material 812 and heparin or otheranti-thrombotics may be affixed to at least a portion of the stent 802.With this configuration, the rapamycin coated graft material 812 may beutilized to minimize or substantially eliminate smooth muscle cellhyperproliferation and the heparin coated stent may substantially reducethe chance of thrombosis.

The particular polymer(s) utilized depends on the particular materialupon which it is affixed. In addition, the particular drug, agent and/orcompound may also affect the selection of polymer(s). As set forthabove, rapamycin may be affixed to at least a portion of the graftmaterial 812 utilizing the polymer(s) and processes described above. Inanother alternate exemplary embodiment, the rapamycin or any other drug,agent and/or compound may be directly impregnated into the graftmaterial 812 utilizing any number of known techniques.

In yet another alternate exemplary embodiment, the stent-graft may beformed from two stents with the graft material sandwiched therebetween.FIG. 25 is a simple illustration of a stent-graft 900 formed from aninner stent 902, an outer stent 904 and graft material 906 sandwichedtherebetween. The stents 902, 904 and graft material 906 may be formedfrom the same materials as described above. As before, the inner stent902 may be coated with an anti-thrombotic or anti-coagulant such asheparin while the outer stent 904 may be coated with ananti-proliferative such as rapamycin. Alternately, the graft material906 may be coated with any of the above described drugs, agents and/orcompounds, as well as combinations thereof, or all three elements may becoated with the same or different drugs, agents and/or compounds.

In yet another alternate exemplary embodiment, the stent-graft designmay be modified to include a graft cuff. As illustrated in FIG. 26, thegraft material 906 may be folded around the outer stent 904 to formcuffs 908. In this exemplary embodiment, the cuffs 908 may be loadedwith various drugs, agents and/or compounds, including rapamycin andheparin. The drugs, agents and/or compounds may be affixed to the cuffs908 utilizing the methods and materials described above or through othermeans. For example, the drugs, agents and/or compounds may be trapped inthe cuffs 908 with the graft material 906 acting as the diffusionbarrier through which the drug, agent and/or compound elutes. Theparticular material selected as well as its physical characteristicswould determine the elution rate. Alternately, the graft material 906forming the cuffs 908 may be coated with one or more polymers to controlthe elution rate as described above.

Stent-grafts may be utilized to treat aneurysms. An aneurysm is anabnormal dilation of a layer or layers of an arterial wall, usuallycaused by a systemic collagen synthetic or structural defect. Anabdominal aortic aneurysm is an aneurysm in the abdominal portion of theaorta, usually located in or near one or both of the two iliac arteriesor near the renal arteries. The aneurysm often arises in the infrarenalportion of the diseased aorta, for example, below the kidneys. Athoracic aortic aneurysm is an aneurysm in the thoracic portion of theaorta. When left untreated, the aneurysm may rupture, usually causingrapid fatal hemorrhaging.

Aneurysms may be classified or typed by their position as well as by thenumber of aneurysms in a cluster. Typically, abdominal aortic aneurysmsmay be classified into five types. A Type I aneurysm is a singledilation located between the renal arteries and the iliac arteries.Typically, in a Type 1 aneurysm, the aorta is healthy between the renalarteries and the aneurysm and between the aneurysm and the iliacarteries.

A Type II A aneurysm is a single dilation located between the renalarteries and the iliac arteries. In a Type II A aneurysm, the aorta ishealthy between the renal arteries and the aneurysm, but not healthybetween the aneurysm and the iliac arteries. In other words, thedilation extends to the aortic bifurcation. A Type II B aneurysmcomprises three dilations. One dilation is located between the renalarteries and the iliac arteries. Like a Type II A aneurysm, the aorta ishealthy between the aneurysm and the renal arteries, but not healthybetween the aneurysm and the iliac arteries. The other two dilations arelocated in the iliac arteries between the aortic bifurcation and thebifurcations between the external iliacs and the internal iliacs. Theiliac arteries are healthy between the iliac bifurcation and theaneurysms. A Type II C aneurysm also comprises three dilations. However,in a Type II C aneurysm, the dilations in the iliac arteries extend tothe iliac bifurcation.

A Type III aneurysm is a single dilation located between the renalarteries and the iliac arteries. In a Type III aneurysm, the aorta isnot healthy between the renal arteries and the aneurysm. In other words,the dilation extends to the renal arteries.

A ruptured abdominal aortic aneurysm is presently the thirteenth leadingcause of death in the United States. The routine management of abdominalaortic aneurysms has been surgical bypass, with the placement of a graftin the involved or dilated segment. Although resection with a syntheticgraft via transperitoneal or retroperitoneal approach has been thestandard treatment, it is associated with significant risk. For example,complications include perioperative myocardial ischemia, renal failure,erectile impotence, intestinal ischemia, infection, lower limb ischemia,spinal cord injury with paralysis, aorta-enteric fistula, and death.Surgical treatment of abdominal aortic aneurysms is associated with anoverall mortality rate of five percent in asymptomatic patients, sixteento nineteen percent in symptomatic patients, and is as high as fiftypercent in patients with ruptured abdominal aortic aneurysms.

Disadvantages associated with conventional surgery, in addition to thehigh mortality rate, include an extended recovery period associated withthe large surgical incision and the opening of the abdominal cavity,difficulties in suturing the graft to the aorta, the loss of theexisting thrombosis to support and reinforce the graft, theunsuitability of the surgery for many patients having abdominal aorticaneurysms, and the problems associated with performing the surgery on anemergency basis after the aneurysm has ruptured. Further, the typicalrecovery period is from one to two weeks in the hospital, and aconvalescence period at home from two to three months or more, ifcomplications ensue. Since many patients having abdominal aorticaneurysms have other chronic illnesses, such as heart, lung, liverand/or kidney disease, coupled with the fact that many of these patientsare older, they are less than ideal candidates for surgery.

The occurrence of aneurysms is not confined to the abdominal region.While abdominal aortic aneurysms are generally the most common,aneurysms in other regions of the aorta or one of its branches arepossible. For example, aneurysms may occur in the thoracic aorta. As isthe case with abdominal aortic aneurysms, the widely accepted approachto treating an aneurysm in the thoracic aorta is surgical repair,involving replacing the aneurysmal segment with a prosthetic device.This surgery, as described above, is a major undertaking, withassociated high risks and with significant mortality and morbidity.

Over the past five years, there has been a great deal of researchdirected at developing less invasive, percutaneous, e.g., catheterdirected, techniques for the treatment of aneurysms, specificallyabdominal aortic aneurysms. This has been facilitated by the developmentof vascular stents, which can and have been used in conjunction withstandard or thin-wall graft material in order to create a stent-graft orendograft. The potential advantages of less invasive treatments haveincluded reduced surgical morbidity and mortality along with shorterhospital and intensive care unit stays.

Stent-grafts or endoprostheses are now FDA approved and commerciallyavailable. The delivery procedure typically involves advancedangiographic techniques performed through vascular accesses gained viasurgical cutdown of a remote artery, such as the common femoral orbrachial arteries. Over a guidewire, the appropriate size introducerwill be placed. The catheter and guidewire are passed through theaneurysm, and, with the appropriate size introducer housing astent-graft, the stent-graft will be advanced along the guidewire to theappropriate position. Typical deployment of the stent-graft devicerequires withdrawal of an outer sheath while maintaining the position ofthe stent-graft with an inner-stabilizing device. Most stent-grafts areself-expanding; however, an additional angioplasty procedure, e.g.,balloon angioplasty, may be required to secure the position of thestent-graft. Following the placement of the stent-graft, standardangiographic views may be obtained.

Due to the large diameter of the above-described devices, typicallygreater than twenty French (3F=1 mm), arteriotomy closure requiressurgical repair. Some procedures may require additional surgicaltechniques, such as hypogastric artery embolization, vessel ligation, orsurgical bypass, in order to adequately treat the aneurysm or tomaintain flow to both lower extremities. Likewise, some procedures willrequire additional, advanced catheter directed techniques, such asangioplasty, stent placement, and embolization, in order to successfullyexclude the aneurysm and efficiently manage leaks.

While the above-described endoprostheses represent a significantimprovement over conventional surgical techniques, there is a need toimprove the endoprostheses, their method of use and their applicabilityto varied biological conditions. Accordingly, in order to provide a safeand effective alternate means for treating aneurysms, includingabdominal aortic aneurysms and thoracic aortic aneurysms, a number ofdifficulties associated with currently known endoprostheses and theirdelivery systems must be overcome. One concern with the use ofendoprostheses is the prevention of endo-leaks and the disruption of thenormal fluid dynamics of the vasculature. Devices using any technologyshould preferably be simple to position and reposition as necessary,should preferably provide an acute fluid tight seal, and shouldpreferably be anchored to prevent migration without interfering withnormal blood flow in both the aneurysmal vessel as well as branchingvessels. In addition, devices using the technology should preferably beable to be anchored, sealed, and maintained in bifurcated vessels,tortuous vessels, highly angulated vessels, partially diseased vessels,calcified vessels, odd shaped vessels, short vessels, and long vessels.In order to accomplish this, the endoprostheses should preferably beextendable and re-configurable while maintaining acute and long termfluid tight seals and anchoring positions.

The endoprostheses should also preferably be able to be deliveredpercutaneously utilizing catheters, guidewires and other devices whichsubstantially eliminate the need for open surgical intervention.Accordingly, the diameter of the endoprostheses in the catheter is animportant factor. This is especially true for aneurysms in the largervessels, such as the thoracic aorta.

As stated above, one or more stent-grafts may be utilized to treataneurysms. These stent-grafts or endoprostheses may comprise any numberof materials and configurations. FIG. 27 illustrates an exemplary systemfor treating abdominal aortic aneurysms. The system 1000 includes afirst prosthesis 1002 and two second prostheses 1004 and 1006, which incombination, bypass an aneurysm 1008. In the illustrated exemplaryembodiment, a proximal portion of the system 1000 may be positioned in asection 1010 of an artery upstream of the aneurysm 1008, and a distalportion of the system 1000 may be positioned in a downstream section ofthe artery or a different artery such as iliacs 1012 and 1014.

A prosthesis used in a system in accordance with the present inventiontypically includes a support, stent or lattice of interconnected strutsdefining an interior space or lumen having an open proximal end and anopen distal end. The lattice also defines an interior surface and anexterior surface. The interior and/or exterior surfaces of the lattice,or a portion of the lattice, may be covered by or support at least onegasket material or graft material.

In preferred embodiments of the invention, a prosthesis is moveablebetween an expanded or inflated position and an unexpanded or deflatedposition, and any position therebetween. In some exemplary embodimentsof the invention, it may be desirable to provide a prosthesis that movesonly from fully collapsed to fully expanded. In other exemplaryembodiments of the invention, it may be desirable to expand theprosthesis, then collapse or partially collapse the prosthesis. Suchcapability is beneficial to the surgeon to properly position orre-position the prosthesis. In accordance with the present invention,the prosthesis may be self-expanding, or may be expandable using aninflatable device, such as a balloon or the like.

Referring back to FIG. 27, the system 1000 is deployed in the infrarenalneck 1010 of the abdominal aorta, upstream of where the artery splitsinto first and second common iliac arteries 1012, 1014. FIG. 27 showsthe first prosthesis or stent gasket 1002 positioned in the infrarenalneck 1010; two second prostheses, 1004, 1006, the proximal ends of whichmatingly engage a proximal portion of stent gasket 1002, and the distalends of which extend into a common iliac artery 1012 or 1014. Asillustrated, the body of each second prosthesis forms a conduit or fluidflow path that passes through the location of the aneurysm 1008. Inpreferred embodiments of the invention, the components of the system1000 define a fluid flow path that bypasses the section of the arterywhere the aneurysm is located.

The first prosthesis includes a support matrix or stent that supports asealing material or foam, at least a portion of which is positionedacross a biological fluid flow path, e.g., across a blood flow path. Inpreferred embodiments of the invention, the first prosthesis, the stent,and the sealing material are radially expandable, and define a hollowspace between a proximal portion of the prosthesis and a distal portionof the prosthesis. The first prosthesis may also include one or morestructures for positioning and anchoring the prosthesis in the artery,and one or more structures for engaging and fixing at least one secondprosthesis in place, e.g., a bypass prosthesis.

The support matrix or stent of the first prosthesis may be formed of awide variety of materials, may be configured in a wide variety ofshapes, and their shapes and uses are well known in the art. Exemplaryprior art stents are disclosed in U.S. Pat. No. 4,733,665 (Palmaz); U.S.Pat. No. 4,739,762 (Palmaz); and U.S. Pat. No. 4,776,337 (Palmaz), eachof the foregoing patents being incorporated herein by reference.

In preferred embodiments of the invention, the stent of the firstprosthesis is a collapsible, flexible, and self-expanding lattice ormatrix formed from a metal or metal alloy, such as nitinol or stainlesssteel. Structures formed from stainless steel may be made self-expandingby configuring the stainless steel in a predetermined manner, forexample, by twisting it into a braided configuration. More preferably,the stent is a tubular frame that supports a sealing material. The termtubular, as used herein, refers to any shape having a sidewall orsidewalls defining a hollow space or lumen extending therebetween; thecross-sectional shape may be generally cylindrical, elliptic, oval,rectangular, triangular, or any other shape. Furthermore, the shape maychange or be deformable as a consequence of various forces that maypress against the stent or prosthesis.

The sealing material or gasket member supported by the stent may beformed of a wide variety of materials, may be configured in a widevariety of shapes, and their shapes and uses are well known in the art.Exemplary materials for use with this aspect of the invention aredisclosed in U.S. Pat. No. 4,739,762 (Palmaz) and U.S. Pat. No.4,776,337 (Palmaz), both incorporated herein by reference.

The sealing material or gasket member may comprise any suitablematerial. Exemplary materials preferably comprise a biodurable andbiocompatible material, including but are not limited to, open cell foammaterials and closed cell foam materials. Exemplary materials includepolyurethane, polyethylene, polytetrafluoroethylene; and other variouspolymer materials, preferably woven or knitted, that provide a flexiblestructure, such as Dacron®. Highly compressible foams are particularlypreferred, preferably to keep the crimped profile low for betterdelivery. The sealing material or foam is preferably substantiallyimpervious to blood when in a compressed state.

The sealing material may cover one or more surfaces of the stent i.e.,may be located along an interior or exterior wall, or both, andpreferably extends across the proximal end or a proximal portion of thestent. The sealing material helps impede any blood trying to flow aroundthe first prosthesis, e.g., between the first prosthesis and thearterial wall, and around one or more bypass prostheses after they havebeen deployed within the lumen of the first prosthesis (described inmore detail below).

In preferred embodiments of the invention, the sealing materialstretches or covers a portion of the proximal end of the stent and alongat least a portion of the outside wall of the stent.

In some embodiments of the invention, it may be desirable for theportion of the sealing material covering the proximal portion of thestent to include one or more holes, apertures, points, slits, sleeves,flaps, weakened spots, guides, or the like for positioning a guidewire,for positioning a system component, such as a second prosthesis, and/orfor engaging, preferably matingly engaging, one or more systemcomponents, such as a second prosthesis. For example, a sealing materialconfigured as a cover or the like, and having a hole, may partiallyocclude the stent lumen.

These openings may be variously configured, primarily to conform to itsuse. These structures promote proper side by side placement of one ormore, preferably multiple, prostheses within the first prosthesis, and,in some embodiments of the invention, the sealing material may beconfigured or adapted to assist in maintaining a certain shape of thefully deployed system or component. Further, these openings may existprior to deployment of the prosthesis, or may be formed in theprosthesis as part of a deployment procedure. The various functions ofthe openings will be evident from the description below. In exemplaryembodiments of the invention, the sealing material is a foam cover thathas a single hole.

The sealing material may be attached to the stent by any of a variety ofconnectors, including a plurality of conventional sutures ofpolyvinylidene fluoride, polypropylene, Dacron®, or any other suitablematerial and attached thereto. Other methods of attaching the sealingmaterial to the stent include adhesives, ultrasonic welding, mechanicalinterference fit and staples.

One or more markers may be optionally disposed in or on the stentbetween the proximal end and the distal end. Preferably, two or moremarkers are sized and/or positioned to identify a location on theprosthesis, or to identify the position of the prosthesis, or a portionthereof, in relation to an anatomical feature or another systemcomponent.

First prosthesis is typically deployed in an arterial passagewayupstream of an aneurysm, and functions to open and/or expand the artery,to properly position and anchor the various components of the system,and, in combination with other components, seal the system or portionsthereof from fluid leaks. For example, the sealing prosthesis may bedeployed within the infrarenal neck, between an abdominal aorticaneurysm and the renal arteries of a patient, to assist in repairing anabdominal aortic aneurysm.

FIGS. 27-29 show an exemplary sealing prosthesis of the presentinvention. Sealing prosthesis 1002 includes a cylindrical or ovalself-expanding lattice, support, or stent 1016, typically made from aplurality of interconnected struts 1018. Stent 1016 defines an interiorspace or lumen 1020 having two open ends, a proximal end 1022 and adistal end 1024. One or more markers 1026 may be optionally disposed inor on the stent between the proximal end 1022 and the distal end 1024.

Stent 1016 may further include at least two but preferably eight (asshown in FIG. 28) spaced apart longitudinal legs 1028. Preferably, thereis a leg extending from each apex 1030 of diamonds formed by struts1018. At least one leg, but preferably each leg, includes a flange 1032adjacent its distal end which allows for the stent 1016 to beretrievable into its delivery apparatus after partial or nearly fulldeployment thereof so that it can be turned, or otherwise repositionedfor proper alignment.

FIG. 29 shows the sealing material 1034 covering the proximal end 1022of stent gasket 1002. In the exemplary embodiment shown in FIG. 29,sealing prosthesis 1002 includes a sealing material 1034 having a firstopening or hole 1036 and a second opening or slit 1038. The gasketmaterial covers at least a portion of the interior or exterior of thestent, and most preferably covers substantially all of the exterior ofthe stent. For example, gasket material 1034 may be configured to coverstent 1016 from the proximal end 1022 to the distal end 1024, butpreferably not covering longitudinal legs 1028.

The sealing material 1034 helps impede any blood trying to flow aroundbypass prostheses 1004 and 1006 after they have been deployed (as shownin FIG. 27) and from flowing around the stent gasket 1002 itself. Forthis embodiment, sealing material 1034 is a compressible member orgasket located along the exterior of the stent 1016 and at least aportion of the interior of the stent 1016.

The second prostheses 1004 and 1006 may comprise stent-grafts such asdescribed with respect to FIG. 24 and may be coated with any of thedrugs, agents and/or compounds as described above. In other words, thestent and/or the graft material may be coated with any of theabove-described drugs, agents and/or compounds utilizing any of theabove-described polymers and processes. The stent gasket 1002 may alsobe coated with any of the above-described drugs, agents and/orcompounds. In other words, the stent and/or sealing material may becoated with any of the above-described drugs, agents and/or compoundsutilizing any of the above-described polymers and processes. Inparticular, rapamycin and heparin may be of importance to prevent smoothmuscle cell hyperproliferation and thrombosis. Other drugs, agentsand/or compounds may be utilized as well. For example drugs, agentsand/or compounds which promote re-endotheliazation may be utilized tofacilitate incorporation of the prosthesis into the living organism.Also, embolic material may be incorporated into the stent-graft toreduce the likelihood of endo leaks.

It is important to note that the above-described system for repairingabdominal aortic aneurysms is one example of such a system. Any numberof aneurysmal repair systems comprising stent-grafts may be coated withthe appropriate drugs, agents and/or compounds, as well as combinationsthereof. For example, thoracic aorta aneurysms may be repaired in asimilar manner. Regardless of the type of aneurysm or its positionwithin the living organism, the components comprising the repair systemmay be coated with the appropriate drug, agent and/or compound asdescribed above with respect to stent-grafts.

A difficulty associated with the treatment of aneurysms, specificallyabdominal aortic aneurysms, is endoleaks. An endoleak is generallydefined as the persistence of blood flow outside of the lumen of thestent-graft, but within the aneurysmal sac or adjacent vascular segmentbeing treated with the stent-graft. Essentially, endoleaks are caused byone of two primary mechanisms, wherein each mechanism has a number ofpossible modalities. The first mechanism involves the incomplete sealingor exclusion of the aneurysmal sac or vessel segment. The secondmechanism involves retrograde flow. In this type of endoleak, blood-flowinto the aneurysmal sac is reversed due to retrograde flow from patentcollateral vessels, particularly the lumbar arteries or the inferiormesenteric artery. This type of endoleak may occur even when a completeseal has been achieved around the stent-grafts. It is also possible thatan endoleak may develop due to stent-graft failure, for example, a tearin the graft fabric.

Endoleaks may be classified by type. A type I endoleak is a perigraftleak at the proximal or distal attachment sites of the stent-grafts.Essentially, this type of endoleak occurs when a persistent perigraftchannel of blood flow develops due to an ineffective or inadequate sealat the ends of the stent-graft. There are a number of possible causes ofa type I endoleak, including improper sizing of the stent-graft,migration of the stent-graft, incomplete stent-graft expansion and anirregular shape of the arterial lumen. A type II endoleak is persistentcollateral blood flow into the aneurysmal sac from a patent branch ofthe aorta. Essentially, the pressure in the aneurysmal sac is lower thanthe collateral branches, thereby causing a retrograde blood flow.Sources of type II endoleaks include the accessory renal arteries, thetesticular arteries, the lumbar arteries, the middle sacral artery, theinferior mesenteric artery and the spinal artery. A type III endoleakmay be caused by a structural failure of the abdominal aortic aneurysmrepair system or its components, for example, the stent-grafts. A typeIII endoleak may also be caused by a junction failure in systemsemploying modular components. Sources of type III endoleaks includetears, rips or holes in the fabric of the stent-graft, improper sizingof the modular components and limited overlap of the modular components.A type IV endoleak is blood flow through the graft material itself. Theblood flow through the pores of the graft material or through smallholes in the fabric caused by the staples or sutures attaching the graftmaterial to the stent. Blood flow through the pores typically occurswith highly porous graft fabrics. A type V endoleak or endotension is apersistent or recurrent pressurization of the aneurysmal sac without anyradiologically detectable endoleak. Possible causes of a type V endoleakinclude pressure transmission by thrombus, highly porous graft material,or the adjacent aortic lumen.

There are a number of possible treatment options for each type ofendoleak described above. The particular treatment option depends mainlyupon the cause of endoleak and the options are not always successful.The present invention is directed to a modification of existingendovascular abdominal aortic aneurysm repair systems or devices, suchas the exemplary devices described herein, that is intended to eliminateor substantially reduce the incidence of endoleaks.

The modification comprises coating at least a portion of the variouscomponents comprising an abdominal aortic aneurysm repair system withdrugs, agents and/or compounds which promote wound healing as describedbelow. For example, portions of the exemplary system 1000, illustratedin FIG. 27, may be coated with one or more drugs, agents and/orcompounds that induce or promote the wound healing process, therebyreducing or substantially reducing the risk of endoleaks. It may beparticularly advantageous to coat the ends of the two second prostheses1004 and 1006 and the entire first prosthesis 1002, as these are themost likely regions for endoleaks. However, coating the entirestent-graft, i.e. graft material and stent, may prove beneficialdepending upon the type of endoleak. Since it is not always possible tostop endoleaks utilizing currently available methods, the use of woundhealing agents, delivered locally, in accordance with the presentinvention may serve to effectively stop or prevent acute and chronicendoleaks. It is important to note that the present invention may beutilized in combination with any abdominal aortic aneurysm repairsystem, or with any other type of graft component where leakage is apotential problem. The present invention may be utilized in conjunctionwith type I, III, IV and V endoleaks.

Normal wound healing essentially occurs in three stages or phases, whichhave a certain degree of overlap. The first phase is cellular migrationand inflammation. This phase lasts for several days. The second phase isthe proliferation of fibroblasts for two to four weeks with new collagensynthesis. The third phase is remodeling of the scar and typically lastsfrom one month to a year. This third phase includes collagen crosslinking and active collagen turnover.

As stated above, there are certain drugs, agents and/or compounds thatmay be delivered locally to the repair site, via the repair system, thatpromotes wound healing which in turn may eliminate or substantiallyreduce the incidence of endoleaks. For example, increased collagenproduction early in wound healing leads to greater wound strength.Accordingly, collagen may be combined with the repair system to increasewound strength and promote platelet aggregation and fibrin formation. Inaddition, certain growth factors may be combined with the repair systemto promote platelet aggregation and fibrin formation as well as toincrease wound strength.

Platelet-derived Growth Factor induces mitoses and is the major mitogenin serum for growth in connective tissue. Platelet Factor 4 is aplatelet released protein that promotes blood clotting by neutralizingheparin. Platelet-derived Growth Factor and Platelet Factor 4 areimportant in inflammation and repair. They are active for humanmonocytes, neutrophils, smooth muscle cells, fibroblasts andinflammation cells. Transforming Growth Factor-β is a part of a complexfamily of polypeptide hormones or biological factors that are producedby the body to control growth, division and maturation of blood cells bythe bone marrow. Transforming Growth Factor-β is found in tissues andplatelets, and is known to stimulate total protein, collagen and DNAcontent in wound chambers implanted in vivo. Transforming GrowthFactor-β in combination with collagen has been shown to be extremelyeffective in wound healing.

A series of reactions take place in the body whenever a blood clotbegins to form. A major initiator of these reactions is an enzyme systemcalled the Tissue Factor/VIIa complex. Accordingly, Tissue Factor/VIIamay be utilized to promote blood clot formation and thus enhance woundhealing. Other agents which are known to initiate thrombus formationinclude thrombin, fibrin, plasminogin-activator initiator, adenosinediphosphate and collagen.

The use of these drugs, agents and/or compounds in conjunction with thevarious components of the repair system may be used to eliminate orsubstantially reduce the incidence of endoleaks through the formation ofblood clots and wound healing.

The stent and/or graft material comprising the components of the system1000 may be coated with any of the above-described drugs, agents and/orcompounds. The above-described drugs, agents and/or compounds may beaffixed to a portion of the components or to all of the componentsutilizing any of the materials and processes described above. Forexample, the drugs, agents and/or compounds may be incorporated into apolymeric matrix or affixed directly to various portions of thecomponents of the system.

The particular polymer(s) utilized depends on the particular materialupon which it is affixed. In addition, the particular drug, agent and/orcompound may also affect the selection of polymer(s).

As described above, other implantable medical devices that may be coatedwith various drugs, agents and/or compounds include surgical staples andsutures. These medical devices may be coated with any of theabove-described drugs, agents and/or compounds to treat variousconditions and/or to minimize or substantially eliminate the organisms'reaction to the implantation of the device.

FIG. 30 illustrates an uncoated or bare surgical staple 3000. The staple3000 may be formed from any suitable biocompatible material having therequisite strength requirements for a given application. Generally,surgical staples comprise stainless steel. FIG. 31 illustrates anexemplary embodiment of a surgical staple 3000 comprising a multiplicityof through-holes 3002, which preferably contain one or more drugs,agents and/or compounds as described above. The one or more drugs,agents and/or compounds may be injected into the through-holes 3002 withor without a polymeric mixture. For example, in one exemplaryembodiment, the through-holes 3002 may be sized such that the one ormore drugs, agents and/or compounds may be injected directly therein andelute at a specific rate based upon the size of the through-holes 3002.In another exemplary embodiment, the one or more drugs, agents and/orcompounds may be mixed with the appropriate polymer, which controls theelution rate, and injected into or loaded into the through-holes 3002.In yet another alternate exemplary embodiment, the one or more drugs,agents and/or compounds may be injected into or loaded into thethough-holes 3002 and then covered with a polymer to control the elutionrate.

FIG. 32 illustrates an exemplary embodiment of a surgical staple 3000comprising a coating 3006 covering substantially the entire surfacethereof. In this embodiment, the one or more drugs, agents and/orcompounds may be directly affixed to the staple 3000 utilizing anynumber of known techniques including spraying or dipping, or the one ormore drugs, agents and/or compounds may be mixed with or incorporatedinto a polymeric matrix and then affixed to the staple 3000.Alternately, the one or more drugs, agents and/or compounds may bedirectly affixed to the surface of the staple 3000 and then a diffusionbarrier may be applied over the layer of one or more drugs, agentsand/or compounds.

Although any number of drugs, agents and/or compounds may be used inconjunction with the surgical staple 3000 to treat a variety ofconditions and/or to minimize or substantially eliminate the organisms'reaction to the implantation of the staple 3000, in a preferredembodiment, the surgical staple 3000 is coated with ananti-proliferative. The advantage of such a device is that theanti-proliferative coating would function as a prophylactic defenseagainst neo-intimal hyperplasia. As described above, neo-intimalhyperplasia often happens at the site of what the body perceives to beinjuries, for example, anastomatic sites, either tissue to tissue ortissue to implant, which are often sites of hyperplastic events. Byutilizing a staple that comprises an anti-proliferative agent, theincidence of neo-intimal hyperplasia may be substantially reduced oreliminated.

Rapamycin is a known anti-proliferative that may be utilized on or inthe surgical staple 3000 and may be incorporated into any of theabove-described polymeric materials. An additional benefit of utilizingrapamycin is its action as an anti-inflammatory. The dual action notonly functions to reduce neo-intimal hyperplasia but inflammation aswell. As used herein, rapamycin includes rapamycin, sirolimus,everolimus and all analogs, derivatives and conjugates that bind FKBP12,and other immunophilins and possesses the same pharmacologic propertiesas rapamycin including inhibition of MTOR.

In yet another alternate exemplary embodiment, the surgical staple 3000may be fabricated from a material, such as a polymeric material, whichincorporates the one or more drugs, agents, and/or compounds. Regardlessof the particular embodiment, the elution rate of the one or more drugs,agents and/or compounds may be controlled as described above.

Referring now to FIG. 33, there is illustrated a section of suturematerial 4000. The suture 4000 may comprise any suitable materialcommonly utilized in the fabrication of both absorbable ornon-absorbable sutures. As illustrated, the suture 4000 comprises acoating 4002 of one or more drugs, agents and/or compounds. As in thecoating on the surgical staple 3000, the one or more drugs, agentsand/or compounds may be applied directly to the suture 4000 or it may bemixed or incorporated into a polymeric matrix and then affixed to thesuture 4000. Also as described above, the one or more drugs, agentsand/or compounds may be affixed to the suture 4000 and then a diffusionbarrier or top coating may be affixed to the one or more drugs, agentsand/or compounds to control the elution or release rate.

FIG. 34 illustrates a section of suture material 4000 impregnated withone or more drugs, agents and/or compounds 4004. The one or more drugs,agents, and/or compounds may be directly impregnated into the suturematerial 4000, incorporated into a polymeric matrix and then impregnatedinto the suture material 4000. Alternately, the one or more drugs,agents and/or compounds may be impregnated into the suture material 4000and then covered with a polymeric material.

In yet another alternate exemplary embodiment, the suture 4000 may beformed from a material, for example, a polymeric material thatincorporates the one or more drugs, agents and/or compounds. Forexample, the one or more drugs, agents, and/or compounds may be mixedwithin the polymer matrix and then extruded and/or formed by a dipmethod to form the suture material.

The particular polymer(s) utilized depend on the particular materialupon which it is affixed. In addition, the particular drug, agent,and/or compound may also affect the selection of polymers. Rapamycin maybe utilized with poly(vinylidenefluoride)/hexafluoropropylene.

The introduction of medical devices into a living organism, and moreparticularly into the vasculature of a living organism, provokes aresponse by the living organism. Typically the benefit provided by themedical device far exceeds any complications associated with the livingorganism's response. Endothelialization is one preferable manner ormeans for making devices fabricated from synthetic materials more bloodcompatible. The endothelium is a single layer of endothelial cells thatforms the lining of all blood vessels. The endothelium regulatesexchanges between blood and surrounding tissues and is surrounded by abasal lamina, i.e. extracellular matrix that separates epithelia layersand other cell types, including fat and muscle cells from connectivetissue.

Endothelial cells cover or line the inner surface of the entire vascularsystem, including the heart, arteries, veins, capillaries and everythingin between. Endothelial cells control the passage of materials and thetransit of white blood cells into and out of the blood stream. While thelarger blood vessels comprise multiple layers of different tissues, thesmallest blood vessels consist essentially of endothelial cells and abasal lamina. Endothelial cells have a high capacity to modify or adjusttheir numbers and arrangement to suit local requirements. Essentially,if it were not for endothelial cells multiplying and remodeling, thenetwork of blood vessel/tissue growth and repair would be impossible.

Even in an adult living organism, endothelial cells throughout thevascular system retain a capacity for cell division and movement. Forexample, if one portion of a vein or artery is missing endothelial cellsthrough damage or disease, neighboring endothelial cells proliferate andmigrate to the affected area in order to cover the exposed surface.Endothelial cells not only repair areas of missing endothelial cells,they are capable of creating new blood vessels. In addition, anddirectly related to the present invention, newly formed endothelialcells will cover implantable medical devices, including stents and othersimilar devices.

As stated above, endothelialization is a means for making devicesfabricated from synthetic materials more blood compatible and thus moreacceptable to the living organism. For the introduction of certainmedical devices anywhere in the vasculature, one goal is the reductionof the thrombogenicity of the medical device. This is device specific,for example, certain medical devices would require thrombus formationfor healing and fixation. Therefore, the endothelialization of thesespecific medical devices is preferable. The source of autologousendothelial cells is crucial and thus an amplification step ispreferable to obtain enough cells to cover the entire exposed surface ofthe medical device regardless of the complexity of design of the medicaldevice. Accordingly, it would be preferable to coat the medical deviceor provide some localized means for the introduction of a chemical,agent, drug, compound and/or biological element for the promotion orproliferation of endothelial cells at the site of the implant.

In accordance with one exemplary embodiment, implantable intraluminalmedical devices, such as stents, may be affixed with, in any of theabove described manners, with vascular endothelial growth factor, VEGF,which acts selectively on endothelial cells. Vascular endothelial growthfactor and its various related isoforms may be affixed directly to anyof the medical devices illustrated and described herein by any of themeans described herein. For example, VEGF may be incorporated into apolymeric matrix or affixed directly to the medical device.

Other factors that promote the stimulation of endothelial cells includemembers of the fibroblast growth factor family. Various agents thataccelerate cellular migration may increase endothelialization, includingagents that upregulate integrins. Nitric oxide may promoteendothelialization. In addition, pro-angiogenic agents may stimulateendothelialization.

Alternately, the medical device may be fabricated from a material whichby its physical material characteristics promotes the migration ofendothelial towards the device. Essentially, since the living organismcreates endothelial cells, any material or coating that attractsendothelial cells would be preferable.

It is generally known in the art that the application of a topcoat of abiocompatible material, for example, a polymer, may be utilized tocontrol the elution of a therapeutic dosage of a pharmaceutical drug,agent and/or compound, or combinations thereof, from a medical devicebase coating, for example, a stent base coating. The basecoat generallycomprises a matrix of one or more drugs, agents and/or compounds and abiocompatible material such as a polymer. The control over elutionresults from either a physical barrier, a chemical barrier, or acombination physical and chemical barrier supplied by the topcoatmaterial. When the topcoat material acts as a physical barrier, theelution is controlled by varying the thickness of the topcoat, therebychanging the diffusion path length for the drugs, agents and/orcompounds to diffuse out of the basecoat matrix. Essentially, the drugs,agents and/or compounds in the basecoat matrix diffuse through theinterstitial spaces in the topcoat. Accordingly, the thicker thetopcoat, the longer the diffusion path, and conversely, the thinner thetopcoat, the shorter the diffusion path. It is important to note thatboth the basecoat and the topcoat thickness may be limited by thedesired overall profile of the medical device. For action as a chemicalbarrier, the topcoat preferably comprises a material that is lesscompatible with the drugs, agents and/or compounds to substantiallyprevent or slow the diffusion, or is less compatible with the basecoatmatrix to provide a chemical barrier the drugs, agents and/or compoundsmust cross prior to being released. It is important to note that theconcentration of the drugs, agents and/or compounds may affect diffusionrate; however, the concentration of the drugs, agents and/or compoundsis dictated to a certain extent by the required therapeutic dosage asdescribed herein.

In one exemplary embodiment, a medical device such as a stent, mayutilize a polymeric material that acts primarily as a chemical barrierfor the control of elution of rapamycin from the stent. As used herein,rapamycin includes rapamycin, sirolimus, everolimus and all analogs,derivatives and conjugates that bind FKBP12, and other immunophilins andpossesses the same pharmacologic properties as rapamycin includinginhibition of mTOR. In this exemplary embodiment, the coating comprisesa basecoat drug, agent and/or compound and polymer matrix with a topcoatthat includes only a polymer. The topcoat polymer and the basecoatpolymer are immiscible or incompatible, thereby creating the chemicalbarrier. Comparisons, however, are made with basecoat and topcoatscomprising the exact same polymers or with polymers containing the sameconstituents in different ratios. Although the primary control mechanismis the chemical barrier, the topcoat also provides a limited physicalbarrier, as will be described subsequently.

In this exemplary embodiment, the basecoat may comprise any suitablefluoropolymer and the topcoat may comprise any suitable acrylate ormethacrylate. In preferred embodiments, the basecoat drugs, agent and/orcompound/polymer matrix comprises the copolymerpolyvinylidenefluoride-co-hexafluoropropylene (PVDF/HFP) as describedabove in detail. The copolymers utilized in this exemplary basecoatembodiment comprises vinylidenefluoride copolymerized withhexafluoropropylene in the weight ratio of sixty weight percentvinyldenefluoride to forty weight percent hexafluoropropylene. Thetopcoat polymer may, as described above, comprise any suitable acrylateor methacrylate. In the preferred embodiment, the topcoat polymercomprises poly(n-butylmethacrylate) or BMA.

PVDF/HFP and BMA are immiscible or incompatible polymers that when mixedand precipitated from solution utilizing known techniques will undergophase separation. It is this incompatibility that allows a topcoat of anacrylic polymer to act as both a chemical barrier (primary mechanism)and physical barrier (secondary mechanism) to the release of a drug,agent and/or compound, such as rapamycin, from the basecoat matrix.

The combination of a PVDF/HFP basecoat and a BMA topcoat offers a numberadvantages over other combinations, including increased durability,increased lubriciousness and increased elution rate control. PVDF/HFP isa flexible polymer. Flexible polymers result in more durable medicaldevice coatings as they tend to move or give as the stent or otherdevice undergoes deformations. Poly(n-butylmethacrylate) or BMA is amore thermoplastic polymer rather than a more elastomeric polymer, andtherefore more rigid than PVDF/HFP. A more rigid polymer equates to aharder surface and a harder surface is a more lubricious surface. Thelubriciousness of the polymer topcoat is important during devicedelivery and deployment as described in detail herein. A lubriciouscoating is particularly advantageous in the delivery of self-expandingstents which typically require the retraction of a delivery sheath. Ifthe coating were not lubricious, the retraction of the delivery sheathmay remove a position of the coating, including the drugs, agents and/orcompounds contained therein. Lubricious coatings are also advantageousfor balloon expandable stents where stent/balloon separation duringdeployment may also remove coating. Acrylic polymers utilized inconjunction with fluoropolymers are excellent chemical and physicalbarriers as described above and thus provide increase elution ratecontrol.

Although the coatings in this exemplary embodiment may be utilized onany number of implantable medical devices as described herein, theexemplary coating embodiments described below are utilized inconjunction with nickel-titanium self-expanding stents.

Referring now to FIG. 49, there is illustrated in vivo drug releasecurves for a number of fluoropolymer/fluoropolymer andfluoropolymer/acrylic coating formulations. The in vivo procedureinvolved evaluating the elution characteristics of rapamycin elutingstents with a number of polymer coating formulations for both thebasecoat and the topcoat. Pigs are an established animal species forintravascular stent studies and accepted for such studies by theappropriate regulatory agencies. This in vivo study utilized male pigsof the species Sus Scrofa and strain Yoorkshire pigs. S.M.A.R.T.™stents, available from Cordis Corporation, were placed into the iliacand femoral arteries, PALMAZ® GENESIS™ stents, available from CordisCorporation, were placed in the renal arteries and CYPHER™ stents,available from Cordis Corporation, were placed in the coronary arteries.Once third of the pigs were euthanized on each of days 2, 4 and 8 andthe stents and surrounding vessels were explanted and analyzed for drugcontent.

The data presented in FIG. 49 represents the release of rapamycin invivo from coated S.M.A.R.T.™ stents, which as described herein, arenickel-titanium stents twenty millimeters in length. The ratio by weightof rapamycin to polymer is thirty/seventy for each PVDF/HFP basecoat andthirty-three/sixty-seven for thepolyethylene-co-vinylacetate/poly(n-butylmethacrylate) (EVA/BMA)basecoat. Curve 4902 represents the elution release rate for a stentcoated with a PVDF/HFP (sixty/forty weight ratio of VDF:HFP) andrapamycin basecoat with a one hundred sixty-seven microgram PVDF/HFP(sixty/forty weight ratio of VDF:HFP) topcoat. Curve 4904 represents theelution release rate for a stent coated with a PVDF/HFP (sixty/fortyweight ratio of VDF:HFP) and rapamycin basecoat with a three hundredfifty microgram PVDF/HFP (eighty-five/fifteen weight ratio of VDF:HFP)topcoat. Curve 4906 represents the elution release rate for a stentcoated with an EVA/BMA and rapamycin basecoat (thirty-three percent EVA,thirty-three percent BMA and thirty-three percent rapamycin) with athree hundred fifty microgram BMA topcoat. Curve 4908 represents theelution release rate for a stent coated with a PVDF/HFP (sixty/fortyweight ratio of VDF:HFP) and rapamycin basecoat with a one hundred fiftymicrogram BMA topcoat. Curve 4910 represents the elution release ratefor a stent coated with a PVDF/HFP (sixty/forty weight ratio of VDF:HFP)and rapamycin basecoat with a three-hundred fifty microgram BMA topcoat.Curve 4912 represents the elution release rate for a stent coated with aPVDF/HFP (sixty/forty weight ratio of VDF:HFP) and rapamycin basecoatwith a four hundred ninety microgram BMA topcoat.

The data represented in FIG. 49 provides an understanding of the elutionrate of rapamycin from various coating combinations. A PVDF/HFP basecoatwith a PVDF/HFP topcoat provides a minor physical barrier to drugelution, and a minimal chemical barrier because the basecoat and topcoatare chemically identical. A topcoat of BMA on a basecoat of EVA/BMAprovides a physical barrier because of the compatibility between theEVA/BMA drug matrix and the BMA topcoat chemistries. The BMA topcoatprovides a slightly more effective barrier to elution because of thedifference in basecoat matrix (EVA/BMA) and topcoat (BMA only)chemistries. The most substantial barrier to the elution of rapamycin,however, is observed with a PVDF/HFP basecoat matrix and a BMA topcoatbecause of the chemical barrier that results from the incompatiblepolymer chemistries. Even within the chemical barrier, however, changesin the topcoat thickness or density, still provide additional levels ofphysical barriers to drug elution, resulting in a coating system thatprovides both a chemical and a physical barrier to control release of apharmaceutical compound as indicated in curves 4908, 4910 and 4912.

The idea of utilizing incompatible polymer chemistries in conjunctionwith varying the thickness of the topcoat in accordance with the presentinvention takes advantage of what may normally be viewed as a negativeaspect of chemical incompatibility to achieve a desired effect. Asindicated in curve 4912, the peak elution release at three days issubstantially less than fifty percent, whereas the peak elution releaseat three days for a PVDF/HFP basecoat and a PVDF/HFP topcoat issubstantially greater than seventy-five percent as indicated in curve4902.

Although demonstrated here with specific examples of a PVDF/HFP(sixty-forty weight ratio of VDF:HFP) copolymer and a BMA polymer, theconcept would apply to any polymer in the family of fluoropolymers incombination with any polymer in the family of acrylics(poly(alkyl)acrylate and poly(alkyl)meth)acrylate).

Referring to FIG. 50, there is illustrated in vitro drug release curvesfor the same fluoropolymer/acrylic coating formulations described abovewith respect to FIG. 49. In in vitro testing procedures, the stents areexposed to continuous flow of a surfactant media for a period oftwenty-four hours. The exposure of the media causes elution of the drug,agent and/or compound (rapamycin in this instance) from the stents. Theflow of media is directed through an ultraviolet/visiblespectrophotometer, and the concentration of rapamycin eluting from thestent is determined as a function of time. Calculations are made basedon the fraction of rapamycin released compared to the total drugcontent, as determined from a drug content assay on stents from the samelot.

The results from the in vitro testing are similar to the results fromthe in vivo testing. Essentially, a review of 5002, 5004, 5006, 5008,5010 and 5012 indicate that once again, the most substantial barrier tothe elution of rapamycin is observed with a PVDF/HFP basecoat matrix anda BMA topcoat because of the chemical barrier that results from theincompatible polymer chemistries and the physical barrier provided bythe thicker topcoat as shown by curve 5012.

It is also interesting to note that a stent coated with a PVDF/HFP(sixty/forty weight ratio of VDF:HFP) basecoat matrix and a BMA topcoatis more durable than a stent coated with a PVDF/HFP (sixty/forty weightratio of VDF:HFP) basecoat matrix and a PVDF/HFP (sixty/forty weightratio of VDF:HFP) topcoat.

The design of a coated implantable medical device that elutes atherapeutic drug, agent and/or compound requires the balancing of anumber of design factors. For example, the addition of a coating to animplantable medical device alters the profile of the device which inturn may have an impact on device delivery. More specifically, theaddition of a coating on a stent increases the diameter of the stent,which in turn may make delivery more difficult. Accordingly, it may bepreferable to minimize the thickness of the coating while increasing theconcentration of the therapeutic drug, agent and/or compound. Increasingthe concentration of the therapeutic drug, agent and/or compound mayincrease its elution rate into the surrounding tissue or bloodstream.Increasing the elution rate may in turn deplete the drug, agent and/orcompound prematurely. Therefore, the present invention provides amechanism whereby drug, agent and/or compound concentrations may beincreased while maintaining control over the elution rate andmaintaining a lower profile. Essentially, the chemical and physicalbarrier provided by the topcoat in the two layer approach provides ameans for increasing drug, agent and/or compound concentrations, ifpreferable, maintaining a lower profile, if preferable, and maintainingmore precise control over elution rates.

In addition, it is important to emphasize the multiple layers; multiplepolymer approach offers the advantages of durability, flexibility andlubriciousness that a single layer approach may not be able to provide.

Vascular diseases include diseases that affect areas of a livingorganism relating to or containing blood vessels. For example, stenosisis a narrowing or constricting of arterial lumen in a living organism(e.g., a human) usually due to atherosclerosis/coronary heart disease(CHD). Restenosis is a recurrence of stenosis after a percuteneousintervention such as angioplasty and stenting. Restenosis typicallyaffects the large arteries of a living organism. The underlyingmechanisms of restenosis comprise a combination of effects from vesselrecoil, negative vascular remodeling, thrombus formation and neointimalhyperplasia. It has been shown that restenosis after balloon angioplastyis mainly due to vessel remodeling and neointimal hyperplasia and afterstenting is mainly due to neo-intimal hyperplasia.

Treatment for stenosis and restenosis varies. Stenosis caused by CHDoften forces individuals to restrict and limit their activity levels inorder to avoid complications, stroke, heart attack, sudden death andloss of limb or function of a limb stemming from the stenosis. Thereconstruction of blood vessels, arteries and veins may also be neededto treat individuals suffering from stenosis and restenosis. Coronarybypass can also be utilized to revascularize the heart and restorenormal blood flow. In other cases, balloon angioplasty may be conductedto increase the orifice size of affected areas. Overall, thesetreatments address the problems associated with stenosis, but they alsocreate a high rate of restenosis that can result in recurrence ofcardiac symptoms and mortality. Moreover, these treatments are notpreventative in nature, and therefore generally are not utilized untilthe patient or individual has already developed stenosis.

One type of stenosis and restenosis is atherosclerosis. Atherosclerosisaffects medium and large arteries and is characterized by a patchy,intramural thickening that encroaches on the arterial lumen and, in mostsevere form, causes obstruction. The atherosclerotic plaque consists ofan accumulation of intracellular and extracellular lipids, smooth musclecells and connective tissue. The earliest lesion of atherosclerosis isthe fatty streak that evolves into a fibrous plaque coating the artery.Atherosclerotic vessels have reduced systolic expansion and abnormalwave propagation. Treatment of atherosclerosis is usually directed atits complications, for example, arrhythmia, heart failure, kidneyfailure, stroke, and peripheral arterial occlusion.

More particularly, atherosclerosis is a thickening and hardening of thearteries and is generally believed to be caused by the progressivebuildup of fatty substances, for example, cholesterol, cellular wasteproducts, inflammatory cells, calcium and other substances in the innerlining or intima of the arteries. The buildup of these substances may inturn stimulate cells in the walls of the affected arteries to produceadditional substances that result in the further buildup of cells.

Atherosclerosis is a slow, complex disease that typically starts inchildhood and progresses as the individual ages. The rate of progressionmay be affected by a number of factors, including blood cholesterollevels, diabetes, obesity, physical inactivity, high blood pressure andtobacco use. This buildup in commonly referred to as plaque and may growlarge enough to significantly reduce blood flow through the affectedarteries.

Essentially, the deposits of the various substances set forth above, andthe proliferation of additional cellular substances or constituentscaused thereby, substantially enlarge the intima, which in turn reducesluminal cross-sectional area and decreases the diameter of the affectedartery or arteries, which in turn reduces the oxygen supply to one ormore organs. The deposits or plaque may also rupture and form bloodclots or thrombi that can completely obstruct blood flow in the affectedartery or break free and travel, emboli, to another part of the body. Ifeither of these events occurs, the individual may suffer a myocardialinfarction if the artery or arteries affected perfuse the heart or astroke if the artery or arteries affected supply blood to the brain. Ifthe artery or arteries affected supply blood to a limb or appendage,gangrene may result.

As indicated above, conventional wisdom holds that heart attacks, forexample, originate from severe blockages created by atherosclerosis. Theincrease of lipids in the artery or arteries and ensuing tissue reactionlead to a narrowing of the affected artery or arteries, which in turn,may result in angina and eventually coronary occlusion, sudden cardiacdeath and thrombotic stroke. Relatively recent research, however, isleading to a shift in understanding atherosclerosis. Researchers nowbelieve that at least some coronary artery disease is an inflammatoryprocess, in which inflammation causes plaque buildup or progression andrupture. These plaques which are prone to rupture, commonly referred toas vulnerable plaques, do not block flow in the affected artery orarteries per se, but rather, much like an abscess, they may be ingrainedin the arterial wall so that they are difficult to detect. Essentially,these vulnerable plaques cannot be seen by conventional angiographyand/or fluoroscopy, and they do not typically cause symptoms such asshortness of breath or pain. Techniques for determining the presence ofvulnerable plaques are, however, improving as discussed subsequently.

For a variety of reasons, these so-called vulnerable plaques are morelikely to erode or rupture, creating emboli and raw or exposed tissuesurfaces that are highly thrombogenic. Accordingly, it is now acceptedthat the majority of cases of acute myocardial infarction, suddencardiac death and thrombolitic stroke result from the disruption ofvulnerable atherosclerotic plaques leading to thrombosis. Therefore,these vulnerable plaques are more dangerous than other plaques thatsimply cause pain, and may be responsible for as much as sixty to eightypercent of all heart attacks.

More specifically, unstable or vulnerable plaques are inflammatoryvascular lesions that develop in atherosclerotic blood vessels.Vulnerable plaques are characterized by active inflammation, cellularhyperplasia and variable degrees of lumen obstruction. Morphologically,vulnerable plaques comprise a fibrous cap in contact with the lumen ofthe vessel overlying a core of lipid and cellular material. Vulnerableplaque lesions are not typically obstructive, in contrast to chronicstable plaques that produce ischemic symptoms. For that reason, they arenot easily detected.

The hallmark of vulnerable plaques is active inflammation withsignificant inflammatory cell infiltration, predominantly T-lymphocytesand macrophage, causing the generation of proteolytic enzymes thatessentially digest the wall of the fibrous cap thereby inducing plaqueinstability and eventually plaque rupture. Plaque rupture exposes highlythrombogenic material in the lipid core to flowing blood leading to therapid development of occlusive thrombi. Ruptured vulnerable plaque, asstated above, is the primary cause of acute coronary and cerebralsyndromes. These include unstable angina, myocardial infarction, bothQ-wave and non-Q-wave myocardial infarction, cerebral stroke andtransient cerebral ischemia. In other words, ruptured vulnerable plaqueaccounts for a significant percentage of cardiovascular morbidity andmortality.

Given the lack of currently available effective technologies fordetecting vulnerable plaque, the treatment of vulnerable plaque istypically initiated only after the plaque has ruptured and clinicalsymptoms have developed. Detection technologies currently underinvestigation include refined magnetic resonance imaging, thermalsensors that measure the temperature of the arterial wall on the premisethat the inflammatory process generates heat, elasticity sensors,intravascular ultrasound, optical coherence tomography, contrast agents,and near-infrared and infrared light. As better diagnostic methodsevolve to identify vulnerable plaque lesions before they rupture, itbecomes possible to treat discrete lesions before dangerous clinicalsymptoms occur. The treatment of vulnerable plaque, however, ispreferably as described below.

Essentially, there are two physiologic processes ongoing in activevulnerable plaque, inflammation and lipid metabolism. Inflammation is anongoing process which includes the inflammation of the fibrous cap andcreating a cap vulnerable to rupture. Lipid metabolism is the formationof a molten or active lipid pool or core comprising a paliable,cholesterolemic lipid material susceptible to rupture. The inflammationprocess is the acute phase and the lipid metabolism is the chronic phaseof vulnerable plaque disease.

A stent or other scaffold structure designed to maintain vessel potencyand comprising a multilaminate coating architecture, including one ormore therapeutic agents, drugs, and/or compounds for treating both theinflammation and lipid metabolism processes, may be utilized toeffectively treat vulnerable plaques. In one exemplary embodiment, astent comprising a coating having a two tier release profile may beutilized to treat both the acute and chronic phases of vulnerableplaque. For example, anti-inflammatory therapeutic agents, such ascorticosteroids, non-steroidal anti-inflammatories, acetylsalicyclicacid, acetaminophen and ibuprofen may be incorporated into the coatingarchitecture for “fast release” and shorter overall duration to addressthe acute phase of vulnerable plaque disease and lipid lowering or lipidmodifying agents may be incorporated into the coating architecture for“slow release” and longer overall duration to address the chronic phaseof vulnerable plaque disease. The entire stent/drug, agent and/orcompound architecture may be released utilizing a variety ofnon-resorbable or resorbable polymers to control, modulate and/oroptimize the delivery profile for optimal physiologic effect. In otherwords, specific therapeutic drug, agent and/or compound deliveryprofiles may be utilized in conjunction with the stent to treat allaspects of vulnerable plaques, for example, fast releaseanti-inflammatory drugs, agents and/or compounds to address theinflammatory rupture of the fibrous cap and slow release lipid loweringor lipid modifying drugs, agents and/or compounds to affect the size andcomposition of the vulnerable plaque lipid pool.

The stent may comprise any suitable scaffold structure, includingballoon expandable stents, constructed from stainless steel or othermetal alloys, and/or self-expanding stents, constructed from nitinol orother shape memory metal alloys. Alternately, the stent may be made fromnon-metallic materials, such as ceramics and/or polymers, which may bebiodegradable. The biodegradable stent would serve as a temporaryscaffold and eventually dissolve over a period of time raging from daysor weeks to months and years. The stent would be mounted on a deliverycatheter and delivered percutaneously through the lumen of a bloodvessel to the site of the vulnerable plaque lesion as described indetail above with respect to treating restenosis. The stent, asdescribed above, is designed to maintain vessel patency and also providestructural support to the weakened or potentially weakened fibrous capand prevent it from rupturing. The stent also provides a means forpreventing further encroachment by the lesion.

Recent research has uncovered that different sex hormones may havedifferent effects on vascular functions. For example, gender differencesin cardiovascular disease have largely been attributed to the protectiveeffects of estrogen in women; premenopausal women have a lower incidenceof Coronary Heart Disease. In particular, estrogen has well-knownbeneficial effects on lipid profile. More importantly, estrogen maydirectly affect vascular reactivity, which is an important component ofatherosclerosis. Recent epidemiological studies suggest that hormonereplacement therapy (HRT) may reduce the risk of coronary-artery diseasein post-menopausal women. More particularly, many epidemiologicalstudies suggest that estrogen replacement therapy (ERT) may becardioprotective in postmenopausal women. The beneficial effects ofthese hormone therapies may also be applicable to males. Unfortunatelythe systemic use of estrogen has limitations due to the possiblehyperplastic effects of estrogen on the uterus and breast in women, andthe feminizing effects in males.

The mechanisms for these beneficial effects are probably multifactorial.Estrogen is known to favorably alter the atherogenic lipid profile andmay also have a direct action on blood vessel walls. Estrogen can haveboth rapid and long-term effects on the vasculature including the localproduction of coagulation and fibrinolytic factors, antioxidants and theproduction of other vasoactive molecules, such as nitric oxide andprostaglandins, all of which are known to influence the development ofvascular disease.

Experimental work suggests that estrogen can also act on the endotheliumand smooth muscle cells either directly or via estrogen receptors inboth men and women. This appears to have an inhibitory effect on manysteps in the atherosclerotic process. With respect to the interventionalcardiology, estrogen appears to inhibit the response to balloon injuryto the vascular wall. Estrogen can repair and accelerate endothelialcell growth in-vitro and in-vivo. Early restoration of endothelial cellintegrity may contribute to the attenuation of the response to injury byincreasing the availability of nitric oxide. This in turn can directlyinhibit the proliferation of smooth muscle cells. In experimentalstudies, estrogen has been shown to inhibit the proliferation andmigration of smooth muscle cells in response to balloon injury. Estrogenhas also proved to inhibit adventitial fibroblast migration, which mayin turn have an effect on negative remodeling.

Accordingly, in addition to the drugs described herein, the local orregional administration of an estrogen, a rapamycin and/or a combinationthereof may be utilized in the treatment or stabilization of vulnerableplaque lesions. Estrogen as utilized herein shall include 17beta-estradiol (chemically described as 1, 3, 5(10)-estradien-3, 17beta-diol having the chemical notation C₁₈H₂₄O₂), synthetic or naturalanalogs or derivatives of 17 beta-estradiol with estrogenic activity, orbiologically active metabolites of 17 beta-estradiol, such as 2 methoxyestradiol. 17 beta-estradiol is a natural estrogen produced in the bodyitself. Accordingly, there should be no biocompatibility issues when 17beta-estradiol is administered locally, regionally or systemically.

17 beta-estradiol is generally regarded as the most potent femalehormone. It is generally known that premenopausal women have a lowerincidence of coronary heart diseas than other individuals and that thesewomen produce higher levels of 17 beta-estradiol. 17 beta-estradiol hasbeen referred to as a natural vasculoprotective agent providing avasculoprotective effect mediated via a number of cellular mechanisms.It has been determined that 17 beta-estradiol may inhibit smooth musclecell proliferation and migration, promote re-endothelialization, andrestore normal endothelial function following vascular injury. Inaddition, 17 beta-estradiol is known to have pleomorphic properties,i.e. the ability to occur in various distinct forms, anti-atherogenicproperties, anti-inflammatory properties and antioxidant properties.

Accordingly, 17 beta-estradiol may be combined with rapamycin to treatvulnerable plaque. The treatment of vulnerable plaque may be achievedthrough the combined effect of two therapeutic agents actingsynergistically through different mechanisms to reduce smooth muscleproliferation, inflammation and atherosclerosis.

The one or more therapeutic drugs, agents and/or compounds utilized incombination with the stent would preferably prevent neointimalhyperplasia that is commonly encountered in stenting and which couldlead to restenosis and device failure as described in detail above. Inaddition, the same or additional therapeutic drugs, agents and/orcompounds would preferably stabilize or passivate the lesion by reducinglocal inflammation and preventing further erosion of the fibrous cap.The one or more therapeutic drugs, agents and/or compounds may bedelivered in a polymer matrix coating applied to the stent struts orembedded into the material forming the stent itself and would releaseinto the vessel wall over a predetermined period of time, preferablyutilizing the dual profile release rate as briefly described above.

In treating both restenosis following vascular injury and treatingvulnerable plaque, it may be advantageous to provide for the regionaldelivery of various drugs, agents and/or compounds in addition to thelocal delivery of various drugs, agents and/or compounds as describedherein. The drugs, agents, and/or compounds delivered regionally may bethe same as those delivered locally or they may be different. Regionaldelivery, as used herein, shall mean delivery to an area greater thanthe area covered by a local delivery device such as those disclosedherein, including stents and other implantable medical devices. Forexample, an infusion catheter may be utilized to administer apredetermined therapeutic dosage or range of dosages of one or moredrugs, agents and/or compounds to a number of sites proximate to thedisease site, for example, stenotic or vulnerable plaque lesions.Essentially, the drug or drugs may be administered proximal to thelesion, distal to the lesion, directly into the lesion or anycombination thereof. The drug or drugs may be administered in any numberof ways, including adventitial injection. The dosage and number ofinjection sites depends on a number of factors, including the type ofdrug, agent and/or compound, the diffusion characteristics of the drug,agent and/or compound and the area in the body that is to be treated. Inpractice, the drug, agent and/or compound is injected into theadventitial tissue proximal and/or distal to the lesion, as well as theadventitial tissue surrounding the lesion, and then distributes axiallyand longitudinally away from the site of injection.

As set forth herein, drug coated stents may be utilized in the treatmentand/or prevention of restenosis and vulnerable plaque. The stents may becoated with any number of drugs or combinations of drugs as describedherein. For example, rapamycin alone or in combination, may be locallydelivered from a stent or other implantable medical devices. In thisexemplary embodiment, the same or different drugs may also be regionallydelivered via a catheter-based device. Essentially, the catheter-baseddevice may be utilized to deliver additional quantities of the drug ordrugs associated with the local delivery device or completely differentdrugs. The regional delivery of drugs may be beneficial for a number ofreasons, including higher dose quantities and broader coverage areas. Inaddition, certain drugs may be more efficacious in injectable formrather than dissolved or suspended in a polymeric coating. Also, drugtherapies may be tailored to the individual patient.

In addition to rapamycin, other drugs that may be regionally deliveredfor the treatment of vulnerable plaque include non-steroidalanti-inflammatories such as aspirin and celecoxib, steroidal agents suchas estrogen, metabolic agents such as troglitazone and anti-coagulantssuch as enoxaparin, probucol, hirudin and apo-A1_(MILANO). Accordingly,these drugs may be utilized alone or in combination with rapamycin.

Any number of catheter-based devices may be utilized for regional drugdelivery. In one exemplary embodiment, the drug delivery devicecomprises a microfabricated surgical device for interventionalprocedures or microneedle. The device is the EndoBionics MicroSyringe™Infusing Catheter available from EndoBionics, Inc., San Leandros Calif.and may be generally characterized set forth below.

The microneedle is inserted substantially normal to the wall of a vessel(artery or vein) to eliminate as much trauma to the patient as possible.Until the microneedle is at the site of an injection, it is positionedout of the way so that it does not scrape against arterial or venouswalls with its tip. Specifically, the microneedle remains enclosed inthe walls of an actuator or sheath attached to a catheter so that itwill not injure the patient during intervention or the physician duringhandling. When the injection site is reached, movement of the actuatoralong the vessel is terminated, and the actuator is controlled to causethe microneedle to be thrust outwardly, substantially perpendicular tothe central axis of a vessel, for instance, in which the catheter hasbeen inserted.

As shown in FIGS. 72A-73B, a microfabricated surgical device 7210includes an actuator 7212 having an actuator body 7212 a and a centrallongitudinal axis 7212 b. The actuator body more or less forms aC-shaped outline having an opening or slit 7212 d extendingsubstantially along its length. A microneedle 7214 is located within theactuator body, as discussed in more detail below, when the actuator isin its unactuated condition (furled state), as illustrated in FIG. 72B.The microneedle is moved outside the actuator body when the actuator isoperated to be in its actuated condition (unfurled state), asillustrated in FIG. 73B.

The actuator may be capped at its proximal end 7212 e and distal end7212 f by a lead end 7216 and a tip end 7218, respectively, of atherapeutic catheter 7220. The catheter tip end serves as a means oflocating the actuator inside a blood vessel by use of a radio opaquecoatings or markers. The catheter tip also forms a seal at the distalend 7212 f of the actuator. The lead end of the catheter provides thenecessary interconnects (fluidic, mechanical, electrical or optical) atthe proximal end 7212 e of the actuator.

Retaining rings 7222 a and 7222 b are located at the distal and proximalends, respectively, of the actuator. The catheter tip is joined to theretaining ring 7222 a, while the catheter lead is joined to retainingring 7222 b. The retaining rings are made of a thin, on the order of tento one hundred microns, substantially rigid material, such as Parylene(types C, D or N), or a metal, for example, aluminum, stainless steel,gold, titanium or tungsten. The retaining rings form a rigidsubstantially C-shaped structure at each end of the actuator. Thecatheter may be joined to the retaining rings by, for example, abutt-weld, an ultra-sonic weld, integral polymer encapsulation or anadhesive such as an epoxy.

The actuator body further comprises a central, expandable section 7224located between retaining rings 7222 a and 7222 b. The expandablesection 7224 includes an interior open area 7226 for rapid expansionwhen an activating fluid is supplied to that area. The central section7224 is made of a thin, semi-rigid or rigid, expandable material, suchas a polymer, for instance, Parylene (types C, D or N), silicone,polyurethane or polyimide. The central section 7224, upon actuation, isexpandable somewhat like a balloon-device.

The central section is capable of withstanding pressures of up to aboutone-hundred atmospheres upon application of the activating fluid to theopen area 7226. The material from which the central section is made ofis rigid or semi-rigid in that the central section returns substantiallyto its original configuration and orientation (the unactuated condition)when the activating fluid is removed from the open area 7226. Thus, inthis sense, the central section is very much unlike a balloon which hasno inherently stable structure.

The open area 7226 of the actuator is connected to a delivery conduit,tube or fluid pathway 7228 that extends from the catheter's lead end tothe actuator's proximal end. The activating fluid is supplied to theopen area via the delivery tube. The delivery tube may be constructed ofTeflon® or other inert plastics. The activating fluid may be a salinesolution or a radio-opaque dye.

The microneedle 7214 may be located approximately in the middle of thecentral section 7224. However, as discussed below, this is notnecessary, especially when multiple microneedles are used. Themicroneedle is affixed to an exterior surface 7224 a of the centralsection. The microneedle is affixed to the surface 7224 a by anadhesive, such as cyanoacrylate. Alternatively, the microneedle may bejoined to the surface 7224 a by a metallic or polymer mesh-likestructure 7230, which is itself affixed to the surface 7224 a by anadhesive. The mesh-like structure may be made of, for instance, steel ornylon.

The 2 microneedle includes a sharp tip 7214 a and a shaft 7214 b. Themicroneedle tip can provide an insertion edge or point. The shaft 7214 bcan be hollow and the tip can have an outlet port 7214 c, permitting theinjection of a pharmaceutical or drug into a patient. The microneedle,however, does not need to be hollow, as it may be configured like aneural probe to accomplish other tasks. As shown, the microneedleextends approximately perpendicularly from surface 7224 a. Thus, asdescribed, the microneedle will move substantially perpendicularly to anaxis of a vessel or artery into which it has been inserted, to allowdirect puncture or breach of vascular walls.

The microneedle further includes a pharmaceutical or drug supplyconduit, tube or fluid pathway 7214 d which places the microneedle influid communication with the appropriate fluid interconnect at thecatheter lead end. This supply tube may be formed integrally with theshaft 7214 b, or it may be formed as a separate piece that is laterjoined to the shaft by, for example, an adhesive such as an epoxy.

The needle 7214 may be a 30-gauge, or smaller, steel needle.Alternatively, the microneedle may be microfabricated from polymers,other metals, metal alloys or semiconductor materials. The needle, forexample, may be made of Parylene, silicon or glass.

The catheter 7220, in use, is inserted through an artery or vein andmoved within a patient's vasculature, for instance, a vein 7232, until aspecific, targeted region 7234 is reached, as illustrated in FIG. 74. Asis well known in catheter-based interventional procedures, the catheter7220 may follow a guide wire 7236 that has previously been inserted intothe patient. Optionally, the catheter 7220 may also follow the path of apreviously-inserted guide catheter (not shown) that encompasses theguide wire. In either case, the actuator is hollow and has a low profileand fits over the guide wire.

During maneuvering of the catheter 7220, well-known methods offluoroscopy or magnetic resonance imaging (MRI) can be used to image thecatheter and assist in positioning the actuator 7212 and the microneedle7214 at the target region. As the catheter is guided inside thepatient's body, the microneedle remains unfurled or held inside theactuator body so that no trauma is caused to the vascular walls.

After being positioned at the target region 7234, movement of thecatheter is terminated and the activating fluid is supplied to the openarea 7226 of the actuator, causing the expandable section 7224 torapidly unfurl, moving the microneedle 7214 in a substantiallyperpendicular direction, relative to the longitudinal central axis 7212b of the actuator body 7212 a, to puncture a vascular wall 7232 a. Itmay take only between approximately one-hundred milliseconds and twoseconds for the microneedle to move from its furled state to itsunfurled state.

The ends of the actuator at the retaining rings 7222 a and 7222 b remainrigidly fixed to the catheter 7220. Thus, they do not deform duringactuation. Since the actuator begins as a furled structure, itsso-called pregnant shape exists as an unstable buckling mode. Thisinstability, upon actuation, produces a large scale motion of themicroneedle approximately perpendicular to the central axis of theactuator body, causing a rapid puncture of the vascular wall without alarge momentum transfer. As a result, a microscale opening is producedwith very minimal damage to the surrounding tissue. Also, since themomentum transfer is relatively small, only a negligible bias force isrequired to hold the catheter and actuator in place during actuation andpuncture.

The microneedle, in fact, travels so quickly and with such force that itcan enter perivascular tissue 7232 b as well as vascular tissue.Additionally, since the actuator is “parked” or stopped prior toactuation, more precise placement and control over penetration of thevascular wall are obtained.

After actuation of the microneedle and delivery of the pharmaceutical tothe target region via the microneedle, the activating fluid is exhaustedfrom the open area 7226 of the actuator, causing the expandable section7224 to return to its original, furled state. This also causes themicroneedle to be withdrawn from the vascular wall. The microneedle,being withdrawn, is once again sheathed by the actuator.

As set forth above, the microneedle or other catheter-based deliverysystems may be utilized to deliver one or more drugs, agents and/orcompounds, including rapamycin, to the site of atherosclerotic plaque.This type of regional delivery may be utilized alone or in combinationwith an implantable medical device with the same or different drugsaffixed thereto. The one or more drugs, agents and/or compounds arepreferably delivered to the adventitial space proximate the lesion.

As described herein, there are a number of advantages to the local orregional delivery of certain drugs, agents and/or compounds via meansother than or in addition to delivery from an implantable medicaldevice. However, the efficacy of the drugs, agents and/or compounds may,to a certain extent, depend on the formulation thereof.

It is typically very difficult to create solution dosage forms of waterinsoluble and lipophilic (having an affinity for and/or tending tocombine with lipids) drugs such as rapamycin without resorting tosubstantial quantities of surfactants, co-solvents and the like. Oftentimes, these excipients (inert substance that acts as a vehicle), suchas Tween 20 and 80, Cremophor and polyethylene glycol (PEG) come withvarying degrees of toxicity to the surrounding tissue. Accordingly, theuse of organic co-solvents such as dimethol sulfoxide (DMSO),N-methylpyrrolidone (NMP) and ethanol need to be minimized to reduce thetoxicity of the solvent. Essentially, the key for a liquid formulationof a water insoluble drug is to find a good combination of excipient andco-solvent, and an optimal range of the additives in the final dosageform to balance the improvement of drug solubility and necessary safetymargins.

As the outstanding results from clinical trials of recent drug elutingstents such as the Cypher® and Taxus® drug eluting stents demonstrated,a prolonged local high concentration and tissue retention of a potentanti-inflammatory and anti-neoplastic agent released from a stentcoating can substantially eliminate the neointimal growth following anangioplasty procedure. Rapamycin, released from the Cypher® stent hasconsistently demonstrated superior efficacy against restenosis afterstent implantation as compared to a bare metal stent. However, there areclinical situations where a non-stent approach for the local delivery orregional delivery may be advantageous, including bifurcated junctions,small arteries and the restenosis of previously implanted stents.Accordingly, there may exist a need for potent therapeutics that onlyneed to be deposited locally or regionally and the drug will exert itspharmacological functions mainly through its good lipophilic nature andlong tissue retention property.

A locally or regionally delivered solution of a potent therapeuticagent, such as rapamycin, offers a number of advantages over asystemically delivered agent or an agent delivered via an implantablemedical device. For example, a relatively high tissue concentration maybe achieved by the direct deposition of the pharmaceutical agent in thearterial wall. Depending on the location of the deposition, a differentdrug concentration profile may be achieved than through that of a drugeluting stent. In addition, with a locally or regionally deliveredsolution, there is no need for a permanently implanted device such as astent, thereby eliminating the potential side affects associatedtherewith, such as inflammatory reaction and long term tissue damage. Itis, however, important to note that the locally or regionally deliveredsolution may be utilized in combination with drug eluting stents orother coated implantable medical devices. Another advantage of solutionor liquid formulations lies in the fact that the adjustment of theexcipients in the liquid formulation would readily change the drugdistribution and retention profiles. In addition, the liquid formulationmay be mixed immediately prior to the injection through a pre-packagedmulti-chamber injection device to improve the storage and shelf life ofthe dosage forms.

In accordance with exemplary embodiments of the present invention, aseries of liquid formulations were developed for the local or regionaldelivery of water insoluble compounds such as sirolimus and its analogs,including CCl-779, ABT-578 and everolimus, through weeping balloons andcatheter injection needles. Sirolimus and its analogs are rapamycins,and rapamycin as used herein, includes rapamycin and all analogs,derivatives and congeners that bind FKBP12 and possess the samepharmacologic properties as rapamycin. These liquid formulationsincrease the apparent solubility of the pharmacologically active butwater insoluble compounds by two to four orders of magnitude as comparedto the solubility limits of the compounds in water. These liquidformulations rely on the use of a very small amount of organic solventssuch as Ethanol (typically less than two percent) and a larger amount ofsafe amphiphilic (of or relating to a molecule having a polar, watersoluble group attached to a non-polar, water insoluble hydration chain)excipients such as polyethylene glycol (PEG 200, PEG 400) and vitamin ETPGS to enhance the solubility of the compounds. These liquidformulations of highly water insoluble compounds are stable and readilyflowable at room temperature. Certain excipients, such as Vitamin E TPGSand BHT may be utilized to enhance the storage stability of sirolimuscompounds through their anti-oxidation properties.

Table 8, shown below, summarizes the concentrations of the excipient,the co-solvents and the drug for four different liquid formulations inaccordance with exemplary embodiments of the present invention. Theconcentrations of each constituent were determined by liquidchromatography and are presented as weight by volume figures. As may beseen from Table 8, a 4 mg/ml concentration of sirolimus was achievedwith an ethanol concentration of two percent, a water concentration oftwenty-five percent and a PEG 200 concentration of seventy-five percent.The concentration of ethanol is preferably two or less percent so as toavoid ethanol becoming an active ingredient in the formulation.

TABLE 8.0 Formulation B1 Formulation A1 Sirolimus conc. (mg/mL) 1.79 1.0EtOH conc. (%) 3.83 2 H2O conc. (%) 7.7 25 PEG 200 conc. (%) 88.5 73Sirolimus conc. (mg/mL) 2.0 4 EtOH conc. (%) 2.0 2.0 H2O conc. (%) 25 25PEG 200 conc. (%) 75 75

As set forth above, a liquid formulation comprising 4 mg/ml of sirolimusmay be achieved utilizing PEG 200 as the excipient and ethanol and wateras the co-solvents. This concentration of sirolimus is about fourhundred to about one thousand times higher than the solubility ofsirolimus in water. The inclusion of an effective co-solvent, PEG 200,ensures that the high concentration of sirolimus does not start toprecipitate out of solution until diluted five to ten fold with water.The high concentration of sirolimus is necessary to maintain aneffective and high local concentration of sirolimus after delivery tothe site. The liquid formulations are flowable at room temperature andare compatible with a number of delivery devices. Specifically, each ofthese formulations were successfully injected through an infusioncatheter designated by the brand name CRESCENDO™ from CordisCorporation, Miami, Fla., as described in more detail subsequently, andthe EndoBionics Micro Syringen™ Infusion Catheter available fromEndoBionics, Inc., San Leandros, Calif., as described in more detailabove, in porcine studies.

In another exemplary embodiment, the liquid formulation of sirolimuscomprises water and ethanol as co-solvents and Vitamin E TPGS as theexcipient. The liquid formulation was created utilizing the followingprocess. Two hundred milligrams of sirolimus and two grams of ethanolwere added to a pre-weighed twenty milliliter scintillation vial. Thevial was vortexed and sonicated until the sirolimus was completelydissolved. Approximately six hundred milligrams of Vitamin E TPGS wasthen added to the solution of ethanol and sirolimus. The vial wasvortexed again until a clear yellowish solution was obtained. Nitrogengas was then used to reduce the amount of ethanol in the vial toapproximately two hundred twenty-nine milligrams. In a separate vial,three hundred milligrams of Vitamin E TPGS was dissolved in elevenmilliliters of purified water while undergoing vortexing. The Vitamin ETPGS and water solution was then added to the first vial containing thesirolimus, Vitamin E TPGS and ethanol. The first vial was then vortexedvigorously and continuously for three minutes. The resulting sirolimussolution was clear with a foam on top. The foam gradually disappearedafter sitting at room temperature. An HPLC assay of sirolimus indicatedthat the sirolimus concentration in the final solution was 15 mg/ml. Thefinal solution had an ethanol concentration of less than two percent,which as stated above is important so as to maintain ethanol as aninactive ingredient. Accordingly, utilizing Vitamin E TPGS as theexcipient rather than PEG, resulted in a higher concentration ofsirolimus in the final formulation.

Table 9, as shown below, summarizes the composition and visualobservations for aqueous formulations of sirolimus utilizing ethanol,Vitamin E TPGS and water at different ratios. The solutions representedby the data contained in Table 9 were generated using essentially thesame procedure as described above, except that the ratios betweensirolimus and Vitamin E TPGS were varied.

TABLE 9.0 13.3 ml water Vitamin E containing Vitamin E Observation ofGroup # Sirolimus mg TPGS, mg Ethanol mg TPGS, mg final solution 1 202.7642 230 320 Clear 2 205.2 631 260 330 Clear 3 201.1 618 260 600 Clear 4204.1 625 260 590 Clear 5 203.3 618 250 1400 Hazy to clear, Viscous 6204.5 630 250 1420 Clear, viscous

All of the above preparations except for number five remained as stablesolutions at both room temperature and under refrigerated condition. Theresults in Table 9 indicate that, Vitamin E TPGS may be utilized over awide range of concentrations to increase the solubility of sirolimus inan aqueous solution.

In another exemplary embodiment, a liquid formulation of CCl-779, asirolimus analog, is prepared utilizing ethanol, Vitamin E TPGS andwater. This liquid formulation was made under similar conditions as tothat described above. Because of its better solubility in ethanol, only0.8 grams of ethanol was used to dissolve two hundred milligrams ofCCl-779 as opposed to the two grams of sirolimus. After the amount ofethanol was reduced to approximately two hundred thirty milligrams,eleven milliliters of purified water containing three hundred milligramsof Vitamin E TPGS was added to the vial of ethanol and CCl-779. Thecombined solution was vortexed for three minutes and resulted in a clearsolution. An HPLC assay of CCl-779 indicated that the concentration ofCCl-779 in the final solution was 15 mg/ml. The concentration of ethanolin the final solution was less than two percent. Accordingly, theresults are substantially identical to that achieved for the sirolimus.

As stated above, a number of catheter-based delivery systems may beutilized to deliver the above-described liquid formulations. One suchcatheter-based system is the CRESCENDO™ infusion catheter. TheCRESCENDO™ infusion catheter is indicated for the delivery of solutions,such as heparinized saline and thrombolytic agents selectively to thecoronary vasculature. The infusion catheter may also be utilized for thedelivery of the liquid formulations, including the liquid solution ofsirolimus, described herein. The infusion region includes an areacomprised of two inflatable balloons with multiple holes at thecatheter's distal tip. The infusion region is continuous with a lumenthat extends through the catheter and terminates at a Luer port in theproximal hub. Infusion of solutions is accomplished by hand injectionthrough an infusion port. The catheter also comprises a guidewire lumenand a radiopaque marker band positioned at the center of the infusionregion to mark its relative position under fluoroscopy.

One of the more common modes of drug degradation involves oxidation.Oxidation may be generally defined as the loss of electrons from amolecule. With respect to organic molecules, oxidation may be more aptlydescribed as an increase in oxygen or decrease in hydrogen content.Antioxidants are molecules that safely interact with free radicals andterminate the potential chain reaction caused by these highly reactiveradicals prior to vital molecule damage. In other words, antioxidantsare essentially scavengers that render free radicals inert prior todamaging molecules or portions of molecules. Accordingly, antioxidantsmay be utilized in drug formulations to prevent or substantially reducedrug degradation. More specifically, antioxidants may be added to oxygensensitive drug and/or drug/polymer solutions utilized to coat drugeluting implantable medical devices, such as stents, as well asinjectable drug solutions to prevent oxidation and reduce drugdegradation. A reduction in degradation due to oxidation will result inan extended shelf life of the drug or drug coated products.

There are a number of different types of antioxidants. The broadestgroup of antioxidants may be generally classified as chain terminators.In one form of oxidation, autoxidation, free radicals, i.e. atoms orgroups of atoms with unpaired electrons, which are formed when oxygeninteracts with certain molecules, can start a chain reaction. Thepropagation of radical chains with the consumption of oxygen allows asingle initiation event to lead to a large number of drug oxidations.Chain terminators form stable radicals, which do not propagate chains.Chain terminators include thiols and phenols. Sacrificial reductants arealso antioxidants. Sacrificial reductants are compounds that are moreeasily oxidized than the molecule that is to be protected, which in thepresent invention is the drug molecule. Sacrificial reductants includesulfites and Ascorbic Acid. Yet another form of antioxidant includesperoxide quenchers. Peroxide quenchers include mannitol.

The effectiveness of antioxidants depends upon a number of factors. Insome circumstances a single antioxidant may provide the desired effect.However, in other circumstances, combinations of antioxidants mayprovide strong synergistic effects. In accordance with the presentinvention, various antioxidants may be utilized alone or in combinationto prevent drug degradation. In addition to their antioxidant effect,the antioxidants may also provide therapeutic effects. For example, drugeluting medical devices with antioxidants may improve long-term vascularpatency by preventing neointimal hyperplasia if sufficiently high ortherapeutic dosages are utilized. Ascorbic Acid, BHT and/or Tocopherol,all antioxidants, may reduce neointimal hyperplasia by preventing freeradical formation or being a scavenger for free radicals. In addition,any number of antioxidants, such as Tocopherol may also be utilized as alubricant.

In accordance with another exemplary embodiment of the presentinvention, a series of injectable formulations were developed for thelocal or regional delivery of taxanes for the treatment of coronaryartery disease. Taxanes include paclitaxel and docetaxel. In onepreferred embodiment of the invention, the therapeutic agent ispaclitaxel, a compound which disrupts microtubule formation by bindingto tubulin to form abnormal mitotic spindles. Briefly, paclitaxel is ahighly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93:2325,1971) which has been obtained from the harvested and dried bark of Taxusbrevifolia (Pacific Yew) and Taxomyces Andreanae and Endophytic Fungusof the Pacific Yew (Stierle et al., Science 60:214-216,-1993).“Paclitaxel” (which should be understood herein to include prodrugs,analogues and derivatives such as, for example, TAXOL®, TAXOTERE®,Docetaxel, 10-desacetyl analogues of paclitaxel and3′N-desbenzoyl-3′N-t-butoxy carbonyl analogues of paclitaxel) may bereadily prepared utilizing techniques known to those skilled in the art(see e.g., Schiff et al., Nature 277:665-667, 1979; Long and Fairchild,Cancer Research 54:4355-4361, 1994; Ringel and Horwitz, J. Natl. CancerInst. 83(4):288-291, 1991; Pazdur et al., Cancer Treat. Rev.19(4):351-386, 1993; WO 94/07882; WO 94/07881; WO 94/07880; WO 94/07876;WO 93/23555; WO 93/10076; WO94/00156; WO 93/24476; EP 590267; WO94/20089; U.S. Pat. Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137;5,202,448; 5,200,534; 5,229,529; 5,254,580; 5,412,092; 5,395,850;5,380,751; 5,350,866; 4,857,653; 5,272,171; 5,411,984; 5,248,796;5,248,796; 5,422,364; 5,300,638; 5,294,637; 5,362,831; 5,440,056;4,814,470; 5,278,324; 5,352,805; 5,411,984; 5,059,699; 4,942,184;Tetrahedron Letters 35(52):9709-9712, 1994; J. Med. Chem. 35:4230-4237,1992; J. Med. Chem. 34:992-998, 1991; J. Natural Prod. 57(10):1404-1410,1994; J. Natural Prod. 57(11):1580-1583, 1994; J. Am. Chem. Soc.110:6558-6560, 1988), or obtained from a variety of commercial sources,including for example, Sigma Chemical Co., St. Louis, Mo. (T7402—fromTaxus brevifolia).

Representative examples of such paclitaxel derivatives or analoguesinclude 7-deoxy-docetaxol, 7,8-cyclopropataxanes, N-substituted2-azetidones, 6,7-epoxy paclitaxels, 6,7-modified paclitaxels,10-desacetoxytaxol, 10-deacetyltaxol (from 10-deacetylbaccatin III),phosphonooxy and carbonate derivatives of taxol, taxol 2′,7-di(sodium1,2-benzenedicarboxylate,10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives,10-desacetoxytaxol, Protaxol(2′- and/or 7-O-ester derivatives), (2′-and/or 7-O-carbonate derivatives), asymmetric synthesis of taxol sidechain, fluoro taxols, 9-deoxotaxane, (13-acetyl-9-deoxobaccatine III,9-deoxotaxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol,Derivatives containing hydrogen or acetyl group and a hydroxy andtert-butoxycarbonylamino, sulfonated 2′-acryloyltaxol and sulfonated2′-O-acyl acid taxol derivatives, succinyltaxol,2′-.gamma.-aminobutyryltaxol formate, 2′-acetyl taxol, 7-acetyl taxol,7-glycine carbamate taxol, 2′-OH-7-PEG(5000)carbamate taxol, 2′-benzoyland 2′,7-dibenzoyl taxol derivatives, other prodrugs (2′-acetyl taxol;2′,7-diacetyltaxol; 2′ succinyltaxol; 2′-(beta-alanyl)-taxol); 2′gamma-aminobutyryltaxol formate; ethylene glycol derivatives of2′-succinyltaxol; 2′-glutaryltaxol; 2′-(N,N-dimethylglycyl)taxol;2′-(2-(N,N-dimethylamino)propionyl)taxol; 2′ orthocarboxybenzoyl taxol;2′ aliphatic carboxylic acid derivatives of taxol, Prodrugs{2′(N,N-diethylaminopropionyl)taxol, 2′(N,N-dimethylglycyl)taxol,7(N,N-dimethylglycyl)taxol, 2′,7-di-(N,N-dimethylglycyl)taxol,7(N,N-diethylaminopropionyl)taxol,2′,7-di(N,N-diethylaminopropionyl)taxol, 2′-(L-glycyl)taxol,7-(L-glycyl)taxol, 2′,7-di(L-glycyl)taxol, 2′-(L-alanyl)taxol,7-(L-alanyl)taxol, 2′,7-di(L-alanyl)taxol, 2′-(L-leucyl)taxol,7-(L-leucyl)taxol, 2′,7-di(L-leucyl)taxol, 2′-(L-isoleucyl)taxol,7-(L-isoleucyl)taxol, 2′,7-di(L-isoleucyl)taxol, 2′-(L-valyl)taxol,7-(L-valyl)taxol, 2′7-di(L-valyl)taxol, 2′-(L-phenylalanyl)taxol,7-(L-phenylalanyl)taxol, 2′,7-di(L-phenylalanyl)taxol,2′-(L-prolyl)taxol, 7-(L-prolyl)taxol, 2′,7-di(L-prolyl)taxol,2′-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2′,7-di(L-lysyl)taxol,2′-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2′,7-di(L-glutamyl)taxol,2′-(L-arginyl)taxol, 7-(L-arginyl)taxol, 2′,7-di(L-arginyl)taxol}, Taxolanalogs with modified phenylisoserine side chains, taxotere,(N-debenzoyl-N-tert-(butoxycaronyl)-10-deacetyltaxol, and taxanes (e.g.,baccatin III, cephalomannine, 10-deacetylbaccatin III, brevifoliol,yunantaxusin and taxusin).

As described above, it is generally very difficult to create solutionformulations of water insoluble and lipophilic drugs such as paclitaxel,including analogs and derivatives, without resorting to substantialamounts of surfactants, co-solvents and the like. Typically, excipientssuch as Tween 20, Tween 80, cremaphor and polyethylene glycol havevarying degrees of toxicity relative to the surrounding tissue.Accordingly, the use of these agents and organic co-solvents such asDMSO, NMP and ethanol need to be minimized to reduce the toxicity of thesolution relative to the surrounding tissue. Essentially, the key to asuccessful injectable formulation of a water insoluble compound is tofind a good combination or balance of excipient and co-solvent and anoptimal range of the additives in the final dosage form to balance theimprovement of drug solubility and necessary safety margin.

A series of injectable formulations of paclitaxel are disclosed hereinfor local or regional delivery through weeping balloons, catheterinjection needles and other catheter-based delivery systems as describedherein. Such injectable formulations make it possible for the deliveryof pharmaceutically active but water insoluble compounds through acatheter-based device. The injectable formulations may be solutions orsuspensions depending on the dosage. In these formulations, thesolubility of the drug may be increased by several orders of magnitudecompared to the solubility limits of the compounds in water.

These injectable formulations rely on the use of a very small amount oforganic solvents, such as ethanol (typically less than two percent), anda larger amount of safe amphiphilic excipients, such as PEG 200, PEG 400and Vitamin E TPGS, to enhance the solubility of the drug. Theseinjectable formulations of highly water insoluble compounds are stableand readily flowable at room temperature. Some excipients, includingVitamin E, Vitamin E TPGS and BHT may also be utilized to enhance thestorage stability of the paclitaxel or other taxane compounds throughtheir anti-oxidation properties as more fully described herein.Alternately, stable suspensions or emulsions of water insolublecompounds may be formed utilizing similar solubility-enhancing agents toobtain a higher drug concentration for local or regional injections. ThepH value of these suspensions or emulsions may be adjusted to improvethe stability of the formulations. These suspension formulations may bemore likely to maintain a more sustained release for the drug at theinjection site as compared with the solution formulations.

Table 17, shown below, summarizes a number of injectable liquidformulations of paclitaxel utilizing combinations of ethanol, PEG 400and water. Specifically, the formulations set forth in Table 17 weremade and analyzed for their concentrations of its various constituents.The concentrations are determined by liquid chromatography and arepresented as weight by volume figures. The concentration of ethanol ispreferably two or less percent so as to avoid ethanol becoming an activeingredient in the formulation. With the concentration of paclitaxel at0.5 mg/ml and a PEG 400 concentration of fifty percent, the finalsolution has a medium viscosity. Higher concentrations of PEG 400 andpaclitaxel resulted in more viscous solutions. When the concentration ofpaclitaxel is greater than 1 mg/ml and the solution is diluted with purewater, the paclitaxel precipitates out of solution. Each of theseformulations may be successfully injected through the Cordis CRESCENDO™infusion catheter and the EndoBionics Micro Syringe™ infusion catheter.

TABLE 17 Paclitaxel conc. Ethanol conc. PEG 400 Observation of Group #(mg/ml) (mg/ml) (%) final solution 1 0.5 0 50 Medium viscosity 2 0.5 0100 Viscous 3 1 0 100 Viscous 4 5 2 100 Viscous

In another exemplary embodiment, a liquid or injectable formulation ofpaclitaxel is made utilizing ethanol, PEG 400 and water, and ethanol,Vitamin E TPGS, PEG400 and water. In making the first formulation, 100mg of paclitaxel is added to 400 μl of ethanol in a pre-weighed 20 mlscintillation vial. The mixture of paclitaxel and ethanol is vortexedand heated in a 60 degree C. bath for ten minutes. Once the drug iscompletely solubilized, 20 ml of PEG 400 is then added to make the finalpaclitaxel concentration 5 mg/ml. This solution remained clear. In aseparate experiment, a series of 20 ml scintillation vials containingVitamin E TPGS are heated or warmed up in a 50 degree C. water bath forten minutes. Concurrently, distilled water is also warmed in a 50 degreeC. water bath. Once the Vitamin E TPGS was melted in each vial, thedistilled water is added into the Vitamin E TPGS vials and vortexed forone minute and left to stand in the water bath for two hours. The finalconcentrations of Vitamin E TPGS in water were one, five and fifteenpercent. The paclitaxel stock solution (5 mg/ml) described herein wasthen mixed with the Vitamin E TPGS solutions to make the finalpaclitaxel formulations. The results are listed in Table 18 given below.In a preferred embodiment, the solution comprises 1.25 mg/ml paclitaxel,3.75 percent Vitamin E TPGS, 0.5 percent ethanol and twenty-five percentPEG 400. This solution is clear and has a low viscosity and thus may beeasily utilized with catheter-based systems.

TABLE 18 Paclitaxel Vitamin E Ethanol PEG conc. TPGS conc. conc. 400Observation of Group # (mg/ml) (%) (%) (%) final solution 1 1.25 3.750.5 25 Clear, low viscosity 2 1.7 5.0 0.7 33 Clear, med viscosity 3 2.57.5 1.0 50 Clear, med viscosity 4 5 0 2 100 Clear, viscous

In yet another exemplary embodiment, aqueous formulations of paclitaxelutilizing ethanol, Vitamin E TPGS and water were made at differentratios. The formulations were made utilizing the same procedure asdescribed above with the exception that PEG 400 was omitted from theformulations. The compositions and observations for the final solutionare set forth in Table 19 given below. All of the preparations set forthin Table 19 were clear solutions upon mixing and vortexing. Once thetemperature of the solution gradually cooled down to room temperature,all formulations except that from group number one became a cloudysuspension of paclitaxel and Vitamin E TPGS.

TABLE 19 Paclitaxel Vitamin E Ethanol conc. TPGS conc. Observation ofGroup # (mg/ml) conc. (%) (%) final formulation 1 1 7.5 2 Hazy to Clear2 5 7.5 2 Stable suspension 3 10 7.5 2 Stable suspension 4 15 7.5 2Stable suspension

The utility of such an injectable paclitaxel suspension is that it maybe injected through an EndoBionics Micro Syringe™ infusion catheter andpotentially provide a more sustained release of paclitaxel from theinjection site. With the presence of precipitated Vitamin E TPGS, thetoxicity of paclitaxel will likely be lessened as well. Other excipientssuch as additional anti-oxidants and stabilizers may also be added tothe formulation to increase the shelf life without significantlyaltering the properties of the formulations.

Alternatively, solutions of paclitaxel and its analogs may be made witha good solvent such as ethanol or acetone, with or without the additionof other cryo-protective excipients such as mannitol, sucrose etc. Theresultant drug solution may be lyophilized by a programmed coolingprocedure such as those built in a commercial freeze-dryer. Alyophilization process may be used to remove ethanol or acetone frompaclitaxel/Vitamin E TPGS solutions to prepare a porous lyophilizedcake.

As may be seen from the above data, a true liquid formulation ofpaclitaxel is disclosed for up to 2.5 mg/ml, which is about 1000 foldhigher than the solubility of paclitaxel in water. The inclusion of aneffective co-solvent, PEG 200/PEG 400, functions to prevent such a highconcentration of paclitaxel from precipitating out of solution untildiluted five to ten fold. Such a high concentration is preferred so asto maintain an effective and high local concentration of paclitaxelafter delivery to the local site with a small injection volume. Thesolution formulation is flowable at room temperature, and as set forthherein, is compatible with any number of catheter-based deliverysystems. The viscosity of the injectable formulation can be adjusted bychanging the mixture ratio of PEG and Vitamin E TPGS. Also, additionalexcipients may be included without substantially affecting the viscosityof the final injection solution. Viscosity is the key to minimizing thepotential damage of the arterial wall at the site of the injection.

It is important to note that the concept of injectable formulations maybe oriented to other taxane compounds. For example, any paclitaxelanalogs may be formulated using the disclosed agents and methodologies.Depending on the water solubility of the compound, a wide range of safesolvent and excipient selections and amounts such as acetone,cyclodextrin can be selected to optimize the formulation. Anti-oxidativecompounds such as Vitamin E mixtures, Vitamin E TPGS and BHT can be usedto increase the storage stability of the liquid formulations. Amounts offormulations excipients such as mannitol, sucrose, trehelose, may beused to produce stable lyophilized formulations. Amounts of amphiphiliccompounds such as Vitamin E TPGS can be adjusted to modulate the tissuediffusion and retention of the drug after local delivery.

As stated above, there are clinical situations where a non-stentapproach for the local delivery may be advantageous, such as the casesof bifurcation junction, small arteries, and restenosis of previousplaced stents. There may exist a need for potent therapeutics that onlyneed to be deposited locally and the drug will exert its pharmacologicalfunctions mainly through its good lipophilic nature and long tissueretention property. Typical examples include sirolimus and paclitaxel,and potentially other taxane compounds. A locally delivered solution ofpotent therapeutics may have a number of advantages, as set forth below,when compared to a drug eluting stent. A relatively high tissueconcentration may be achieved by direct deposition of the pharmaceuticalagent in the arterial wall. Depending on the location of the deposition,a different drug concentration profile may be achieved than that of adrug eluting stent. No need of a permanently implanted device such as astent and other potential side effects such as inflammatory reaction andlong term tissue damage. Adjustment of the excipients in the liquidformulation would readily change the drug distribution and retentionprofiles. The liquid formulations may be mixed immediately prior to theinjection through a pre-packaged multi-chamber injection needle toimprove the storage and shelf life of the dosage forms. Such liquidformulations may also become a viable approach for the treatment ofvulnerable plaques (VP), and prophylactic treatment of stroke. Dependingon the drug used, such liquid formulations may also have huge advantagesover local delivery of micro- and nano-spheres in areas of dosagestability, avoidance of using large bore needle and needle clogging.

Any number of antioxidants may be utilized to prevent drug degradation.The selection of an antioxidant depends on a number of factors such asthe oxygen sensitive drug substance chemistry, the polymer coatingsystem, if one is utilized, and variation of the antioxidant'sconcentration to achieve the desired effect to prevent oxidation andreduce drug degradation. Examples of antioxidants include AscorbylPalmitate, Ascorbic Acid, Butylated Hydroxytoluene (BHT), Tocopherols,Ascorbic Acid isomers and/or derivatives, Sulfurous Acid salts, Thiolderivatives, Butylated Hydroxanisole (BHA), Nordihydroguaiaretic Acidand Propyl Gallate. Other potential antioxidants include AcetylCysteine, Adipic Acid, Citric Acid, Cysteine, Disoduim Editic Acid(EDTA), Fumaric Acid, Gutamic Acid, Malic Acid, Sodium FormaldehydeSulfoxylate, Sodium Metabisulfite, Sodium Sulfite, Sodium Thosulfate,Tartaric Acid, Thioglycerol, Thiourea and Toluene Sulfonic Acid.

Although the antioxidants may be utilized with any number of drugs,including all the drugs described herein, exemplary embodiments of theinvention are described with respect to rapamycin and more specifically,drug eluting implantable medical devices comprising rapamycin. Asbriefly set forth above, molecules or specific portions of molecules maybe particularly sensitive to oxidation. In rapamycins, the conjugatedtriene moiety of the molecule is particularly susceptible to oxidation.Essentially, oxygen breaks the carbon chain of the conjugate trienemoiety and the bioactivity of the rapamycin is degraded. In addition, asis typical with oxidation processes, the drug is broken down into one ormore different compounds. Accordingly, it may be particularlyadvantageous to mix or co-mingle an antioxidant with the rapamycin.Specifically, in order to achieve the best results, it is important toco-mingle the antioxidant and the drug to the greatest extent possible.More importantly, the physical positioning of the antioxidant proximateto the drug is the key to success. The antioxidant preferably remainsfree to combine with oxygen so that the oxygen does not break up themoiety and ultimately degrade the drug. Given that the rapamycin may beincorporated into a polymeric coating or matrix, it is particularlyimportant that the antioxidant be maintained proximate to the drugrather than the polymer(s). Factors that influence this include theconstituents of the polymeric matrix, the drug, and how the polymer/drugcoating is applied to the implantable medical device. Accordingly inorder to achieve the desired result, selection of the appropriateantioxidant, the process of mixing all of the elements and theapplication of the mixture is preferably tailored to the particularapplication.

In accordance with an exemplary embodiment, a number of antioxidantswere tested to determine their efficacy in preventing the degradation ofrapamycin, or more specifically, sirolimus. Screening experiments wereperformed to evaluate the solubility of various antioxidants intetrahydroxyfuran (THF) solutions containing sirolimus and thepercentage of antioxidant required to prevent oxidation of sirolimusalone and in a basecoat polymeric matrix. THF is the solvent in whichsirolimus may be dissolved. It is important to note that other solventsmay be utilized. Two sets of controls were utilized. Control #1comprises solutions of THF and sirolimus and/or polymers with noantioxidant, and Control #2 comprises solutions of THF and sirolimusand/or polymers, wherein the THF contains a label claim of 250 ppm ofBHT as a stabilizer from the vendor of THF. In other words, the BHT isan added constituent of the THF solvent to prevent oxidation of thesolvent. Table 10 shown below is a matrix of the various mixtures. Allpercentages are given as weight/volume.

TABLE 10.0 Target Antioxidant Target Antioxidant % Grams/ % Grams/Antioxidant Antioxidant 50 mL Antioxidant 50 mL Ascorbic Acid 0.02 0.010.5 0.25 Ascorbyl 0.01 0.005 0.02 0.01 Palmitate BHT 0.005 0.0025 0.020.01 Tocopherol 0.05 0.025 0.075 0.0375 Control #1 0.0 0.0 0.0 0.0Control #2 250 0.0 0.0 0.0 ppm BHT

Table 11, shown below, identifies the samples for evaluation. Allpercentages are given as weight/volume. The samples in Table 11 containno polymer. Table 12, also shown below, identifies the samples forevaluation with the solutions now comprising polymers, including PBMAand PEVA as described herein.

TABLE 11.0 Solutions with Sirolimus Only - No Polymers SAMPLE ID #ACTUAL % ANTIOXIDANT AA1A 0.026 Ascorbic Acid AA2A 0.50 Ascorbic AcidAP1A 0.01 Ascorbyl Palmitate AP2A 0.02 Ascorbyl Palmitate BHT1A 0.006BHT BHT2A 0.02 BHT C2A Control #2 - 250 ppm BHT TP1A 0.048 TocopherolTP2A 0.082 Tocopherol C1A Control #1

TABLE 12.0 Solutions with Sirolimus and Polymers SAMPLE ID # ACTUAL %ANTIOXIDANT AA1B 0.022 Ascorbic Acid AA2B 0.508 Ascorbic Acid AP1B 0.01Ascorbyl Palmitate AP2B 0.02 Ascorbyl Palmitate BHT1B 0.006 BHT BHT2B0.02 BHT C2B Control #2 - 250 ppm BHT TP1B 0.054 Tocopherol TP2B 0.102Tocopherol C1B Control #1

As set forth above, each of the samples in Tables 11 and 12 were testedto determine the solubility of the various antioxidants as well as theireffectiveness in preventing drug degradation. All of the antioxidantswere soluble in both the solvent with sirolimus solutions and thesolvent with sirolimus and polymer solutions. The solubility of each ofthe antioxidants was determined by a visual inspection of the testsamples.

Table 13, as shown below, identifies the chosen samples that wereevaluated for drug content (percent label claim or % LC) after five (5)days in an oven set at a temperature of sixty degrees C. (60° C.). Thesamples were evaluated after five (5) days utilizing a drug testingassay for silolimus. In the exemplary embodiment, a HPLC assay wasutilized. The important numbers are the percent label claim number (%LC) of the solutions that indicates how much of the drug remains or isrecovered. The antioxidants, BHT, Tocopherol, and/or Ascorbic Acidprovided significant protection against the harsh environmentalconditions of the test. Lower % LC numbers are evident in solutionssamples that do not contain an antioxidant.

TABLE 13.0 Solutions with Sirolimus and Polymers after 5 days 60° C.storage SAMPLE ID # ACTUAL % ANTIOXIDANT % LC AA2B 0.508 Ascorbic Acid96.4 AP2B 0.02 Ascorbyl Palmitate 82.5 BHT2B 0.02 BHT 94.8 TP2B 0.102Tocopherol 97.3 C2B Control #2 - 250 ppm BHT 99.5 C1B Control #1 70.0C1B Control #1 69.2

As shown below, Table 14 provides the % LC results for the sampleswithout polymers and Table 15 provides the % LC results for the sampleswith polymer after four (4) weeks of sixty degrees C. (60° C.).

TABLE 14.0 CALCULATED THEORETICAL SAMPLE RESULTS CONCENTRATION ID #(μg/ml) (μg/ml) % LC AA1A 1155.56 1669.2 69.2 AA2A 1280.90 1669.2 76.7AP1A 851.45 1669.2 51.0 AP2A 939.36 1669.2 56.3 BHT1A 437.38 1669.2 26.2BHT2A 1434.98 1669.2 86.0 TP1A 1335.58 1669.2 80.0 TP2A 1618.61 1669.297.0 C1A #1 608.64 1669.2 36.5 C1A #2 552.57 1669.2 33.1 C2A #1 1794.701669.2 107.5 C2A #2 1794.67 1669.2 107.5

TABLE 15.0 CALCULATED THEORETICAL SAMPLE RESULTS CONCENTRATION ID #(μg/ml) (μg/ml) % LC AA1B 884.95 1669.2 53.0 AA2B 1489.70 1669.2 89.2AP1B 743.98 1669.2 44.6 AP2B 906.76 1669.2 54.3 BHT1B 595.18 1669.2 35.7BHT2B 1396.55 1669.2 83.7 TP1B 1177.30 1669.2 70.5 TP2B 1695.45 1669.2101.6 C1B #1 490.56 1669.2 29.4 C1B #2 470.15 1669.2 28.2 C2B #1 1807.441669.2 108.3 C2B #2 1810.41 1669.2 108.5

As seen from a review of the % LC or drug recovery enumerated in Tables14 and 15, higher percent concentrations of Tocopherol, BHT, and/orAscorbic Acid provide significant protection against the harshenvironmental conditions of the test. However, higher % LC numbers areevident in all controls containing 250 ppm BHT due to possible solutionevaporation of the samples from loose caps on the samples in the 60° C.storage condition.

Additional samples were tested under ambient conditions, rather than at60° C., and using the same compositions; however, the test period wasexpanded to seven weeks. The results are given in Table 16, shown below.

TABLE 16.0 CALCULATED THEORETICAL SAMPLE RESULTS CONCENTRATION ID #(μg/ml) (μg/ml) % LC C1A 1248.04 1669.2 74.8 C2A 1578.15 1669.2 94.5C1BMS 1376.46 1669.2 82.5 C1BMS 1377.20 1669.2 82.5 C2B 1633.07 1669.297.8 TP1A 1635.54 1669.2 98.0 TP2A 1632.05 1669.2 97.8 TP1B 1631.751669.2 97.8 TP2B 1621.64 1669.2 97.2 AA1A 1590.17 1669.2 95.3 AA2A1578.21 1669.2 94.5 AA1B 1598.79 1669.2 95.8 AA2B 1592.47 1669.2 95.4AP1A 1429.76 1669.2 87.7 AP2A 1415.83 1669.2 84.8 AP1B 1472.45 1669.288.2 AP2B 1480.31 1669.2 88.7 BHT1A 1527.18 1669.2 91.5 BHT2A 1601.721669.2 96.0 BHT1B 1579.50 1669.2 94.6 BHT2B 1614.52 1669.2 96.7

As may be seen from a review of Table 16, the results are substantiallysimilar to those obtained for five (5) days and four (4) weeks at sixtydegrees C. (60° C.) % LC data. Accordingly, in a preferred exemplaryembodiment, Tocopherol, BHT and/or Ascorbic Acid may be utilized tosubstantially reduce drug degradation due to oxidation.

Referring to FIG. 75, there is illustrated in graphical format, theresults of the same drug screening as described above with the solutionapplied to a cobalt-chromium, 18 mm stent. In this test, two sets ofsolution samples were utilized, one with sirolimus and polymer solutioncontaining the antioxidant and one with sirolimus and polymer solutioncontaining no antioxidant. The antioxidant utilized was 0.02 weightpercent BHT per total basecoat solids. The test was utilized todetermine the percent drug content change over a time period of 0 to 12weeks under two conditions; namely, 40° C. with 75 percent relativehumidity, and ambient conditions (25° C.). As can be seen from thechart, the addition of BHT to the solution lessens drug degradation atboth 8 weeks and 12 weeks under ambient conditions. Accordingly, if onedoes not stabilize the base coat solution, other process techniques mustbe utilized; namely, refrigeration and/or vacuum drying.

Although shown and described is what is believed to be the mostpractical and preferred embodiments, it is apparent that departures fromspecific designs and methods described and shown will suggest themselvesto those skilled in the art and may be used without departing from thespirit and scope of the invention. The present invention is notrestricted to the particular constructions described and illustrated,but should be constructed to cohere with all modifications that may fallwithin the scope of the appended claims.

1. An aqueous formulation of a therapeutic agent comprising: paclitaxelin a concentration of 1.25 mg/ml; 3.75 percent vitamin E d-alphatocopheryl polyethylene glycol succinate (Vitamin E TPGS); 0.5 percentethanol; 25 percent poly(ethylene glycol) 400; and 70 percent water, theaqueous formulation comprising a stable solution for at least one ofdirect local or regional delivery into arterial tissue.